Publications by authors named "John L Goudreau"

34 Publications

Heterozygous VPS13A and PARK2 Mutations in a Patient with Parkinsonism and Seizures.

Case Rep Neurol 2021 May-Aug;13(2):341-346. Epub 2021 Jun 11.

Department of Neurology, Michigan State University, East Lansing, Michigan, USA.

Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA. Neurologic examinations showed cognitive impairment and marked parkinsonian signs. MRI showed bilateral basal ganglia gliosis. He was found to have a novel heterozygous mutation in the VPS13A gene, in addition a heterozygous mutation in the PARK2 gene. His clinical picture was atypical for typical chorea-acanthocytosis (ChAc). The compound heterozygous mutations of VPS13A and PARK2 provide the most plausible explanation for this patient's clinical symptoms. This case adds to the phenotypic diversity of ChAc. More research is needed to fully understand the roles of epistatic interactions on phenotypic expression of neurodegenerative diseases.
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http://dx.doi.org/10.1159/000515805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255736PMC
June 2021

BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson's Disease.

Neurotherapeutics 2020 10 19;17(4):1785-1795. Epub 2020 Nov 19.

Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI, 49503-2532, USA.

Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659). The primary measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and its motor component (UPDRS-III). Groups were divided by genotype and treatment regimen (levodopa monotherapy vs levodopa with other medications vs no levodopa). T allele carriers were associated with worse UPDRS outcomes compared to C/C subjects when treated with levodopa monotherapy (+ 6 points, p = 0.02) and to T allele carriers treated with no levodopa treatment strategies (UPDRS: + 8 points, p = 0.01; UPDRS-III: + 6 points, p = 0.01). Similar effects of worse outcomes associated with levodopa monotherapy were observed in the BDNF rs11030094, rs10501087, and rs1491850 SNPs. This study suggests the levodopa monotherapy strategy is associated with worse disease outcomes in BDNF rs6265 T carriers. Pending prospective validation, BDNF variants may be precision medicine factors to consider for symptomatic treatment decisions for early-stage PD patients.
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http://dx.doi.org/10.1007/s13311-020-00965-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851242PMC
October 2020

Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction.

BMC Vet Res 2020 Sep 25;16(1):356. Epub 2020 Sep 25.

Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 784 Wilson Road, East Lansing, MI, 48824, USA.

Background: Pituitary pars intermedia dysfunction (PPID) develops slowly in aged horses as degeneration of hypothalamic dopaminergic neurons leads to proliferation of pars intermedia (PI) melanotropes through hyperplasia and adenoma formation. Dopamine (DA) concentrations and tyrosine hydroxylase (TH) immunoreactivity are markedly reduced in PI tissue of PPID-affected equids and treatment with the DA receptor agonist pergolide results in notable clinical improvement. Thus, we hypothesized that pergolide treatment of PPID-affected horses would result in greater DA and TH levels in PI tissue collected from PPID-affected horses versus untreated PPID-affected horses. To test this hypothesis, pituitary glands were removed from 18 horses: four untreated PPID-affected horses, four aged and four young horses without signs of PPID, and six PPID-affected horses that had been treated with pergolide at 2 µg/kg orally once daily for 6 months. DA concentrations and TH expression levels in PI tissues were determined by high performance liquid chromatography with electrochemical detection and Western blot analyses, respectively.

Results: DA and TH levels were lowest in PI collected from untreated PPID-affected horses while levels in the pergolide treated horses were similar to those of aged horses without signs of PPID.

Conclusions: These findings provide evidence of restoration of DA and TH levels following treatment with pergolide. Equine PPID is a potential animal model of dopaminergic neurodegeneration, which could provide insight into human neurodegenerative diseases.
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http://dx.doi.org/10.1186/s12917-020-02565-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517620PMC
September 2020

Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.

Neurology 2019 10 4;93(14):e1328-e1338. Epub 2019 Sep 4.

From the Departments of Neurology (M.A.S., R.B., S.B., R.L., A.Y.H., G.B.) and Medicine (E.A.M.), Massachusetts General Hospital, Boston; University of Cincinnati (A.J.E.), OH; Rush University (C.G.G.), Chicago, IL; Michigan State University (J.L.G.), East Lansing; Struthers Parkinson's Center (S.A.P.), Minneapolis, MN; Boston University (M.H.S.-H.), MA; University of Rochester (A.R.), NY; University of Miami (J.M.H.), FL; Brigham and Women's Hospital (G.C.C.), Boston, MA; Yale University School of Medicine (D.S.R.), New Haven, CT; and Department of Nutrition (A.A.), Harvard School of Public Health, Boston, MA.

Objective: To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.

Methods: The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.

Results: Inosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [ < 0.001] and +98% [ < 0.001], respectively) than on placebo (in contrast to men: +10% [ = 0.6] and +14% [ = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson's Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo ( = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate ( = -0.52; = 0.001), and with greater increases in plasma antioxidant capacity ( = -0.44; = 0.006). No significant associations were observed in men.

Conclusions: Inosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.

Clinicaltrialsgov Identifier: NCT00833690.

Classification Of Evidence: This study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.
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http://dx.doi.org/10.1212/WNL.0000000000008194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814412PMC
October 2019

Bdnf variant is associated with milder motor symptom severity in early-stage Parkinson's disease.

Parkinsonism Relat Disord 2018 08 9;53:70-75. Epub 2018 May 9.

Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Saint Mary's, Grand Rapids, MI, USA. Electronic address:

Introduction: Parkinson's disease (PD) progression is heterogeneous. Variants in PD-related genes may alter disease progression or severity. We examined if the single nucleotide variant rs6265 in the gene Bdnf alters clinical phenotype in early-stage, unmedicated PD.

Methods: A retrospective analysis was conducted using data collected in the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) study. DNA samples (n = 217) were genotyped for the Bdnf rs6265 variant, and the primary endpoint was time to initiate levodopa. The Parkinson's Progression Markers Initiative (PPMI) was used for validation (n = 383).

Results: The primary endpoint of time to initiate levodopa was associated with a delay in subjects with two copies of the rs6265 minor (Met66) allele (HR: 4.9; 95% CI: 1.3-18.8). Secondary endpoints were not different among genotypes. PPMI subjects with two Met66 alleles demonstrated significantly lower total and part III Movement Disorder Society - United Parkinson's Disease Rating Scale (MDS-UPDRS) scores at baseline, as well as more tremor-related symptoms, but not a delay in initiation of maintenance pharmacotherapy.

Conclusions: Data from two distinct, unmedicated, early-stage PD cohorts suggest that carrying two copies of the rs6265 Met66 allele (∼4% of the population) is associated with less severity in motor symptoms and potentially a slower rate of progression.
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http://dx.doi.org/10.1016/j.parkreldis.2018.05.003DOI Listing
August 2018

Metabolism of Dopamine in Nucleus Accumbens Astrocytes Is Preserved in Aged Mice Exposed to MPTP.

Front Aging Neurosci 2017 12;9:410. Epub 2017 Dec 12.

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States.

Parkinson disease (PD) is prevalent in elderly individuals and is characterized by selective degeneration of igrotriatal opmine (NSDA) neurons. Interestingly, not all dopamine (DA) neurons are affected equally by PD and aging, particularly esoimbic (ML) DA neurons. Here, effects of aging were examined on presynaptic DA synthesis, reuptake, metabolism and neurotoxicant susceptibility of NSDA and mesolimbic dopamine (MLDA) neurons and astrocyte DA metabolism. There were no differences in phenotypic markers of DA synthesis, reuptake or metabolism in NSDA or MLDA neurons in aged mice, but MLDA neurons displayed lower DA stores. Astrocyte metabolism of DA to 3-methoxytyramine (3-MT) in the striatum was decreased in aged mice, but was maintained in the nucleus accumbens. Despite diminished DA vesicular storage capacity in MLDA neurons, susceptibility to acute neurotoxicant exposure was similar in young and aged mice. These results reveal an age- and neurotoxicant-induced impairment of DA metabolic activity in astrocytes surrounding susceptible NSDA neurons as opposed to maintenance of DA metabolism in astrocytes surrounding resistant MLDA neurons, and suggest a possible therapeutic target for PD.
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http://dx.doi.org/10.3389/fnagi.2017.00410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732926PMC
December 2017

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

J Parkinsons Dis 2017 ;7(1):117-127

Department of Biostatistics, The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, Houston, TX, USA.

Background: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients.

Objective: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline.

Methods: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually.

Results: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p < 0.001), Ambulatory Capacity (p < 0.001), and the Rankin (p = 0.002).

Conclusions: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.
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http://dx.doi.org/10.3233/JPD-160965DOI Listing
November 2017

FosB and ΔFosB expression in brain regions containing differentially susceptible dopamine neurons following acute neurotoxicant exposure.

Brain Res 2016 Oct 24;1649(Pt A):53-66. Epub 2016 Aug 24.

Genetics Program, Michigan State University, East Lansing, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA. Electronic address:

Parkinson disease (PD) is characterized by progressive neuronal degeneration, in particular nigrostriatal dopamine (NSDA) neurons and consequent deficits in movement. In mice and non-human primates, NSDA neurons preferentially degenerate following exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tuberoinfundibular (TI) DA neurons, in contrast, appear to be unaffected in PD and recover following acute MPTP exposure-induced injury (Behrouz et al., 2007; Benskey et al., 2012). The recovery of the TIDA neurons is dependent on de novo protein synthesis and positively correlated with an increase in parkin mRNA and protein expression (Benskey et al., 2012, 2015). Inhibition of parkin upregulation renders TIDA neurons susceptible to degeneration following MPTP exposure. In addition to parkin, other potentially protective proteins are likely to be differentially regulated in TIDA and NSDA neurons following neurotoxicant exposure. The regulation of potential transcription factors for parkin and other neuroprotective pathway genes are of interest since they may provide novel targets for PD disease modifying therapies. As such, we sought to determine if there are time-dependent differences in the expression of AP-1 transcription factors c-Fos, c-Jun, FosB, ΔFosB and JunD in TIDA and NSDA neurons of mice following acute MPTP exposure. We observed that both FosB and ΔFosB expression increase in brain regions containing TIDA, but not NSDA neurons. Furthermore, the nuclear and long-term expression of ΔFosB is consistent with its role as a transcription factor that may influence parkin transcription, which may underlie the unique ability of TIDA neurons to recovery from an injury that leads NSDA neurons to degeneration.
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http://dx.doi.org/10.1016/j.brainres.2016.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035640PMC
October 2016

Choice of dopaminergic therapy among early, mild Parkinson disease subjects in North America.

J Neurol Sci 2016 Jul 16;366:74-81. Epub 2016 Apr 16.

Department of Neurology, Georgia Regent's University, 1120 15th St, Augusta, GA 30912, USA. Electronic address:

The choice of dopaminergic therapy in early Parkinson disease (PD) is an important clinical decision, yet factors influencing this decision have not been extensively studied. We sought to investigate the factors that may be associated with the choice of dopaminergic therapy at the NINDS Exploratory Trials in PD (NET-PD) Long-Term Study-1 (LS1). NET-PD LS1 was a clinical trial of creatine versus placebo in participants with early, mild PD on stable doses of dopaminergic therapy. Baseline data from 1616 out of the 1741 participants were evaluated using univariable and multivariable logistic or generalized logit regression analyses for available factors associated with the choice of dopaminergic therapy. The dopaminergic therapy choice was determined as: (i) therapy that subjects recalled taking 180days before the study; (ii) therapy at baseline; and (iii) the longest duration of therapy reported by participants. Younger age, higher education level, longer length of time since PD diagnosis and use of an adjunctive, non-dopaminergic or monoamine oxidase inhibitor medication were associated with more frequent use of dopamine agonist compared to levodopa or combination therapy.
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http://dx.doi.org/10.1016/j.jns.2016.04.021DOI Listing
July 2016

Reduced Noradrenergic Signaling in the Spleen Capsule in the Absence of CB and CB Cannabinoid Receptors.

J Neuroimmune Pharmacol 2016 12 10;11(4):669-679. Epub 2016 Jun 10.

Neuroscience Program, Michigan State University, East Lansing, MI, USA.

The spleen is a visceral organ that contracts during hypoxia to expel erythrocytes and immune cells into the circulation. Spleen contraction is under the control of noradrenergic sympathetic innervation. The activity of noradrenergic neurons terminating in the spleen capsule is regulated by α2-adrenergic receptors (AR). Interactions between endogenous cannabinoid signaling and noradrenergic signaling in other organ systems suggest endocannabinoids might also regulate spleen contraction. Spleens from mice congenitally lacking both CB and CB cannabinoid receptors (Cnr1 /Cnr2 mice) were used to explore the role of endocannabinoids in spleen contraction. Spleen contraction in response to exogenous norepinephrine (NE) was found to be significantly lower in Cnr1 /Cnr2 mouse spleens, likely due to decreased expression of capsular α1AR. The majority of splenic Cnr1 mRNA expression is by cells of the spleen capsule, suggestive of post-synaptic CB receptor signaling. Thus, these studies demonstrate a role for CB and/or CB in noradrenergic splenic contraction.
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http://dx.doi.org/10.1007/s11481-016-9689-2DOI Listing
December 2016

Comparison of the structure, function and autophagic maintenance of mitochondria in nigrostriatal and tuberoinfundibular dopamine neurons.

Brain Res 2015 Oct 2;1622:240-51. Epub 2015 Jul 2.

Genetics Program, Michigan State University, East Lansing, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA. Electronic address:

A pathological hallmark of Parkinson׳s disease (PD) is progressive degeneration of nigrostriatal dopamine (NSDA) neurons, which underlies the motor symptoms of PD. While there is severe loss of midbrain NSDA neurons, tuberoinfundibular (TI) DA neurons in the mediobasal hypothalamus (MBH) remain intact. In the present study, confocal microscopic analysis revealed that mitochondrial content and numbers of mitophagosomes were lower in NSDA neuronal cell bodies in the substantia nigra pars compacta (SNpc) compared to TIDA neuronal cell bodies in the arcuate nucleus (ARC) of C57BL/6J male mice. Mitochondrial respiration, mass, membrane potential and morphology were determined using bioenergetic, flow cytometric and transmission electron microscopic analyses of synaptosomes isolated from discrete brain regions containing axon terminals of NSDA and TIDA neurons. Maximum and spare respiratory capacities, and mitochondrial mass were lower in synaptosomal mitochondria derived from the striatum (ST) as compared with the MBH, which correlated with lower numbers of mitochondria per synaptosome in these brain regions. In contrast, there was no regional difference in mitochondrial basal, maximum or spare respirations following inhibition of Complex I activity with rotenone. These results reveal that higher numbers of viable mitochondria are correlated with more extensive autophagic mitochondrial quality maintenance in TIDA neurons as compared with NSDA neurons.
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http://dx.doi.org/10.1016/j.brainres.2015.06.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562814PMC
October 2015

Methylmercury impairs canonical dopamine metabolism in rat undifferentiated pheochromocytoma (PC12) cells by indirect inhibition of aldehyde dehydrogenase.

Toxicol Sci 2015 Apr 19;144(2):347-56. Epub 2015 Jan 19.

*Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824 *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824.

The environmental neurotoxicant methylmercury (MeHg) disrupts dopamine (DA) neurochemical homeostasis by stimulating DA synthesis and release. Evidence also suggests that DA metabolism is independently impaired. The present investigation was designed to characterize the DA metabolomic profile induced by MeHg, and examine potential mechanisms by which MeHg inhibits the DA metabolic enzyme aldehyde dehydrogenase (ALDH) in rat undifferentiated PC12 cells. MeHg decreases the intracellular concentration of 3,4-dihydroxyphenylacetic acid (DOPAC). This is associated with a concomitant increase in intracellular concentrations of the intermediate metabolite 3,4-dihydroxyphenylaldehyde (DOPAL) and the reduced metabolic product 3,4-dihydroxyethanol. This metabolomic profile is consistent with inhibition of ALDH, which catalyzes oxidation of DOPAL to DOPAC. MeHg does not directly impair ALDH enzymatic activity, however MeHg depletes cytosolic levels of the ALDH cofactor NAD(+), which could contribute to impaired ALDH activity following exposure to MeHg. The observation that MeHg shunts DA metabolism along an alternative metabolic pathway and leads to the accumulation of DOPAL, a reactive species associated with protein and DNA damage, as well as cell death, is of significant consequence. As a specific metabolite of DA, the observed accumulation of DOPAL provides evidence for a specific mechanism by which DA neurons may be selectively vulnerable to MeHg.
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http://dx.doi.org/10.1093/toxsci/kfv001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372664PMC
April 2015

Parkinson's disease severity and use of dopaminergic medications.

Parkinsonism Relat Disord 2015 Mar 15;21(3):297-9. Epub 2014 Dec 15.

Department of Neurology, Michigan State University, 804 Service Rd, Room A217, USA.

Background: The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected.

Objective: The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD.

Methods: A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life.

Results: The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine.

Conclusion: This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy.
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http://dx.doi.org/10.1016/j.parkreldis.2014.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340731PMC
March 2015

The role of parkin in the differential susceptibility of tuberoinfundibular and nigrostriatal dopamine neurons to acute toxicant exposure.

Neurotoxicology 2015 Jan 20;46:1-11. Epub 2014 Nov 20.

Neuroscience Program, Michigan State University, East Lansing, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA; Department of Neurology, Michigan State University, East Lansing, MI, USA.

Parkinson disease causes degeneration of nigrostriatal dopamine (DA) neurons, while tuberoinfundibular DA neurons remain unaffected. A similar pattern is observed following exposure to 1-methy-4-phenyl-1,2,3,6-tetrahydropyradine (MPTP). The mechanism of tuberoinfundibular neuronal recovery from MPTP is associated with up-regulation of parkin protein. Here we tested if parkin mediates tuberoinfundibular neuronal recovery from MPTP by knocking-down parkin in tuberoinfundibular neurons using recombinant adeno-associated virus (rAAV), expressing a short hairpin RNA (shRNA) directed toward parkin. Following knockdown, axon terminal DA and tyrosine hydroxylase (TH) concentrations were analyzed 24h post-MPTP administration. rAAV-shRNA-mediated knockdown of endogenous parkin rendered tuberoinfundibular neurons susceptible to MPTP induced terminal DA loss, but not TH loss, within 24h post-MPTP. To determine if the neuroprotective benefits of parkin up-regulation could be translated to nigrostriatal neurons, rAAV expressing human parkin was injected into the substantia nigra of mice and axon terminal DA and TH concentrations were analyzed 24h post-MPTP. Nigral parkin over-expression prevented loss of TH in the axon terminals and soma of nigrostriatal neurons, but had no effect on terminal DA loss within 24h post-MPTP. These data show that parkin is necessary for the recovery of terminal DA concentrations within tuberoinfundibular neurons following acute MPTP administration, and parkin can rescue MPTP-induced decreases in TH within nigrostriatal neurons.
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http://dx.doi.org/10.1016/j.neuro.2014.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339631PMC
January 2015

Enhanced humoral immunity in mice lacking CB1 and CB2 receptors (Cnr1-/-/Cnr2-/- mice) is not due to increased splenic noradrenergic neuronal activity.

J Neuroimmune Pharmacol 2014 Sep 29;9(4):544-57. Epub 2014 May 29.

Neuroscience Program, Michigan State University, East Lansing, MI, USA.

Peripheral sympathetic noradrenergic neurons originating in the celiac mesenteric plexus have axons that terminate in close proximity to antibody-producing B cells in the spleen. Norepinephrine (NE) released from these neurons is reported to augment antibody production in response to an immune challenge via an action at the β2-adrenergic receptor (β2AR). Cannabinoids are immunosuppressive, and mice lacking CB1 and CB2 receptors (Cnr1(-/-)/Cnr2(-/-) mice) have augmented cell-mediated immune responses. The purpose of this study was to determine if Cnr1(-/-)/Cnr2(-/-) mice also exhibit enhanced humoral immunity and if that is associated with corresponding changes in noradrenergic neurons terminating in the spleen. The results reveal that IgM and IgG are enhanced in Cnr1(-/-)/Cnr2(-/-) mice as compared to WT both in immunologically naïve and lipopolysaccharide (LPS)-treated mice. While the elevated antibody production was correlated with increased expression of β2AR on splenic B cells and increased splenic capsule NE concentrations, the activity of noradrenergic neurons was suppressed in spleens from Cnr1(-/-)/Cnr2(-/-) mice as compared with WT controls. Together, these results suggest that Cnr1(-/-)/Cnr2(-/-) mice exhibit enhanced NE vesicular storage in axon terminals in these neurons, which might limit the NE available to bind β2AR on target cells, such as B cells. The results also demonstrate that enhanced antibody responses in the absence of CB1 and CB2 receptors are not due to increased sympathetic noradrenergic neuronal activity in the spleen.
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http://dx.doi.org/10.1007/s11481-014-9549-xDOI Listing
September 2014

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

JAMA Neurol 2014 Feb;71(2):141-50

Rush University Medical Center, Chicago, Illinois.

Importance: Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).

Objective: To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.

Design, Setting, And Participants: The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.

Interventions: Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.

Main Outcomes And Measures: The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.

Conclusions And Relevance: Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.

Trial Registration: clinicaltrials.gov Identifier: NCT00833690.
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http://dx.doi.org/10.1001/jamaneurol.2013.5528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940333PMC
February 2014

Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein.

Neurotoxicology 2013 Jul 1;37:144-53. Epub 2013 May 1.

Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA.

Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined. Mice were treated with ten injections of either MPTP (20mg/kg; s.c.; every 3.5 days) or saline vehicle (10 ml/kg; s.c.; every 3.5 days). Following a 21 day recovery period, chronic saline- and MPTP-treated mice received an additional injection of either saline (10 ml/kg; s.c.) or MPTP (20mg/kg; s.c.) and were sacrificed 24h later. NSDA neurons displayed significant axon terminal degeneration (as reflected by decreases in DA, tyrosine hydroxylase (TH) and DA transporter concentrations in the striatum) as well as loss of TH-immunoreactive (IR) neurons in the substantia nigra (SN) following MPTP, whereas TIDA neurons revealed no overt axon terminal pathology or loss of TH-IR cell bodies. NSDA neuronal pathology was associated with transient decreases in concentrations of parkin and UCHL-1 protein in the SN, which returned to normal levels by 21 days following cessation of chronic neurotoxicant exposure. Resistance of TIDA neurons to MPTP toxicity was correlated with a transient increase in UCHL-1 and a sustained elevation in parkin in the arcuate nucleus. TIDA neurons represent a DA neuron population with a unique and inherent ability to adapt to acute and chronic toxicant administration with a sustained elevation of the neuroprotective protein parkin. The correlation between the ability to increase parkin and UCHL-1 expression and the resistance of DA neurons to neurotoxicant exposure is consistent with a functional link between these features and an underlying differential susceptibility to toxicant-associated neurodegeneration.
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http://dx.doi.org/10.1016/j.neuro.2013.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982185PMC
July 2013

The role of de novo catecholamine synthesis in mediating methylmercury-induced vesicular dopamine release from rat pheochromocytoma (PC12) cells.

Toxicol Sci 2013 May 19;133(1):125-32. Epub 2013 Feb 19.

Neuroscience Program, Michigan State University, East Lansing, Michigan 48824, USA.

The purpose of this study was to characterize methylmercury (MeHg)-induced dopamine (DA) release from undifferentiated pheochromocytoma (PC12) cells and to examine the potential role for DA synthesis in this process. MeHg caused a significant increase in DA release that was both concentration- and time-dependent. DA release was significantly increased by 2µM MeHg at 60min and by 5µM MeHg at 30min; 1µM MeHg was without effect. Because DA release induced by 5µM MeHg was associated with a significant percentage of cell death at 60 and 120min, 2µM MeHg was chosen for further characterization of release mechanisms. MeHg-induced DA release was attenuated but not abolished in the absence of extracellular calcium, whereas the vesicular content depleting drug reserpine (50nM) abolished release. Thus, MeHg-induced DA release requires vesicular exocytosis but not extracellular calcium. MeHg also increased intracellular DA and the rate of DA storage utilization, suggesting a role for DA synthesis in MeHg-induced DA release. The tyrosine hydroxylase inhibitor α-methyltyrosine (300µM, 24h) completely abolished MeHg-induced DA release. MeHg significantly increased DA precursor accumulation in cells treated with 3-hydroxybenzylhydrazine (10µM), revealing that MeHg increases tyrosine hydroxylase activity. Overall, these data demonstrate that MeHg facilitates DA synthesis, increases intracellular DA, and augments vesicular exocytosis.
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http://dx.doi.org/10.1093/toxsci/kft025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627552PMC
May 2013

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Neurogenetics 2013 Feb 20;14(1):11-22. Epub 2013 Jan 20.

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.
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http://dx.doi.org/10.1007/s10048-012-0349-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023541PMC
February 2013

A call for transparent reporting to optimize the predictive value of preclinical research.

Nature 2012 Oct;490(7419):187-91

National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892, USA.

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.
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http://dx.doi.org/10.1038/nature11556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511845PMC
October 2012

Comparison of the D2 receptor regulation and neurotoxicant susceptibility of nigrostriatal dopamine neurons in wild-type and CB1/CB2 receptor knockout mice.

J Neuroimmune Pharmacol 2012 Sep 27;7(3):533-8. Epub 2012 May 27.

Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA.

Motor dysfunctions of Parkinson Disease (PD) are due to the progressive loss of midbrain nigrostriatal dopamine (NSDA) neurons. Evidence suggests a role for cannabinoid receptors in the neurodegeneration of these neurons following neurotoxicant-induced injury. This work evaluates NSDA neurons in CB1/CB2 knockout (KO) mice and tests the hypothesis that CB1/CB2 KO mice are more susceptible to neurotoxicant exposure. NSDA neuronal indices were assessed using unbiased stereological cell counting, high pressure liquid chromatography coupled with electrochemical detection or mass spectrometry, and Western blot. Results reveal that CB1 and CB2 cannabinoid receptor signaling is not necessary for the maintenance of a normally functioning NSDA neuronal system. Mice lacking CB1 and CB2 receptors were found to be equally susceptible to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). These studies support the use of CB1/CB2 KO mice for investigating the cannabinoid receptor-mediated regulation of the NSDA neuronal system in models of PD.
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http://dx.doi.org/10.1007/s11481-012-9375-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479639PMC
September 2012

Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression.

Neurotoxicology 2012 Jun 9;33(3):321-31. Epub 2012 Feb 9.

Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA.

Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed in acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and rotenone rat models of degeneration. It is not known if the resistance of TIDA neurons is a constitutive or induced cell-autonomous phenotype for this unique subset of DA neurons. In the present study, treatment with a single injection of MPTP (20 mg/kg; s.c.) was employed to examine the response of TIDA versus NSDA neurons to acute injury. An acute single dose of MPTP caused an initial loss of DA from axon terminals of both TIDA and NSDA neurons, with recovery occurring solely in TIDA neurons by 16 h post-treatment. Initial loss of DA from axon terminals was dependent on a functional dopamine transporter (DAT) in NSDA neurons but DAT-independent in TIDA neurons. The active metabolite of MPTP, 1-methyl, 4-phenylpyradinium (MPP+), reached higher concentration and was eliminated slower in TIDA compared to NSDA neurons, which indicates that impaired toxicant bioactivation or distribution is an unlikely explanation for the observed resistance of TIDA neurons to MPTP exposure. Inhibition of protein synthesis prevented TIDA neuron recovery, suggesting that the ability to recover from injury was dependent on an induced, rather than a constitutive cellular mechanism. Further, there were no changes in total tyrosine hydroxylase (TH) expression following MPTP, indicating that up-regulation of the rate-limiting enzyme in DA synthesis does not account for TIDA neuronal recovery. Differential candidate gene expression analysis revealed a time-dependent increase in parkin and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) expression (mRNA and protein) in TIDA neurons during recovery from injury. Parkin expression was also found to increase with incremental doses of MPTP. The increase in parkin expression occurred specifically within TIDA neurons, suggesting that these neurons have an intrinsic ability to up-regulate parkin in response to MPTP-induced injury. These data suggest that TIDA neurons have a compensatory mechanism to deal with toxicant exposure and increased oxidative stress, and this unique TIDA neuron phenotype provides a platform for dissecting the mechanisms involved in the natural resistance of central DA neurons following toxic insult.
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http://dx.doi.org/10.1016/j.neuro.2012.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3363356PMC
June 2012

Opioid-mediated regulation of A11 diencephalospinal dopamine neurons: pharmacological evidence of activation by morphine.

Neuropharmacology 2011 Sep 13;61(4):614-21. Epub 2011 May 13.

Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.

Dopamine (DA) neurons of the A11 diencephalospinal system represent the sole source of DA innervation to the spinal cord in mice, serving neuromodulatory roles in the processing of nociceptive input and movement. These neurons originate in the dorso-caudal diencephalon and project axons unilaterally throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn. The density of A11 DA axon terminals in the lumbar region is greater in males compared to females, while in both sexes the activity of neurons terminating in the thoracic spinal cord is greater than those terminating in the lumbar region. The present study was designed to test the hypothesis that A11 DA neurons are activated by opioids. To test this hypothesis, male and female mice were systemically treated with agonists or antagonists acting at the μ-opioid receptor, and spinal cord concentrations of DA and its metabolite DOPAC were determined in the thoracic and lumbar spinal cord using high performance liquid chromatography coupled with electrochemical detection. Systemic administration of the μ-opioid agonist morphine led to a dose- and time-dependent increase in spinal cord DOPAC/DA ratio (an estimate of DA neuronal activity) in both male and female mice, with greater changes occurring in the lumbar segment. Blockade of opioid receptors with the opioid antagonist naloxone reversed the stimulatory effects of morphine on A11 DA neurons in both male and female mice, but had little to no effect on the activity of these neurons when administered alone. Present findings are consistent with the conclusion that spinal cord-projecting axon terminals of A11 DA neurons are activated by opioids in both male and female mice, most likely through a dis-inhibitory mechanism.
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http://dx.doi.org/10.1016/j.neuropharm.2011.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130120PMC
September 2011

Neonatal androgen-dependent sex differences in lumbar spinal cord dopamine concentrations and the number of A11 diencephalospinal dopamine neurons.

J Comp Neurol 2010 Jul;518(13):2423-36

Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA.

A(11) diencephalospinal dopamine (DA) neurons provide the major source of DA innervation to the spinal cord. DA in the dorsal and ventral horns modulates sensory, motor, nociceptive, and sexual functions. Previous studies from our laboratory revealed a sex difference in the density of DA innervation in the lumbar spinal cord. The purpose of this study was to determine whether sex differences in spinal cord DA are androgen dependent, influenced by adult or perinatal androgens, and whether a sex difference in the number of lumbar-projecting A(11) neurons exists. Adult male mice have significantly higher DA concentrations in the lumbar spinal cord than either females or males carrying the testicular feminization mutation (tfm) in the androgen receptor (AR) gene, suggesting an AR-dependent origin. Spinal cord DA concentrations are not changed following orchidectomy in adult male mice or testosterone administration to ovariectomized adult female mice. Administration of exogenous testosterone to postnatal day 2 female mice results in DA concentrations in the adult lumbar spinal cord comparable to those of males. Male mice display significantly more lumbar-projecting A(11) DA neurons than females, particularly in the caudal portion of the A(11) cell body region, as determined by retrograde tract tracing and immunohistochemistry directed toward tyrosine hydroxylase. These results reveal an AR-dependent sex difference in both the number of lumbar-projecting A(11) DA neurons and the lumbar spinal cord DA concentrations, organized by the presence of androgens early in life. The AR-dependent sex difference suggests that this system serves a sexually dimorphic function in the lumbar spinal cord.
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http://dx.doi.org/10.1002/cne.22340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884812PMC
July 2010

Activation of autophagy through modulation of 5'-AMP-activated protein kinase protects pancreatic beta-cells from high glucose.

Biochem J 2010 Jan 15;425(3):541-51. Epub 2010 Jan 15.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.

Chronic hyperglycaemia is detrimental to pancreatic beta-cells by causing impaired insulin secretion and diminished beta-cell function through glucotoxicity. Understanding the mechanisms underlying beta-cell survival is crucial for the prevention of beta-cell failure associated with glucotoxicity. Autophagy is a dynamic lysosomal degradation process that protects organisms against metabolic stress. To date, little is known about the physiological function of autophagy in the pathogenesis of diabetes. In the present study, we explored the roles of autophagy in the survival of pancreatic beta-cells exposed to high glucose using pharmacological and genetic manipulation of autophagy. We demonstrated that chronic high glucose increases autophagy in rat INS-1 (832/13) cells and pancreatic islets, and that this increase is enhanced by inhibition of 5'-AMP-activated protein kinase. Our results also indicate that stimulation of autophagy rescues pancreatic beta-cells from high-glucose-induced cell death and inhibition of autophagy augments caspase-3 activation, suggesting that autophagy plays a protective role in the survival of pancreatic beta-cells. Greater knowledge of the molecular mechanisms linking autophagy and beta-cell survival may unveil novel therapeutic targets needed to preserve beta-cell function.
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http://dx.doi.org/10.1042/BJ20090429DOI Listing
January 2010

Insulin withdrawal-induced cell death in adult hippocampal neural stem cells as a model of autophagic cell death.

Autophagy 2009 Feb 17;5(2):277-9. Epub 2009 Feb 17.

Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824, USA.

The term "autophagic cell death" was coined to describe a form of cell death associated with the massive formation of autophagic vacuoles without signs of apoptosis. However, questions about the actual role of autophagy and its molecular basis in cell death remain to be elucidated. We recently reported that adult hippocampal neural stem (HCN) cells undergo autophagic cell death following insulin withdrawal. Insulin-deprived HCN cells exhibit morphological and biochemical markers of autophagy, including accumulation of Beclin 1 and the type II form of microtubule-associated protein 1 light chain 3 (LC3) without evidence of apoptosis. Suppression of autophagy by knockdown of Atg7 reduces cell death, whereas promotion of autophagy with rapamycin augments cell death in insulin-deficient HCN cells. These data reveal a causative role of autophagy in insulin withdrawal-induced HCN cell death. HCN cells have intact apoptotic capability despite the lack of apoptosis following insulin withdrawal. Our study demonstrates that autophagy is the default cell death mechanism in insulin-deficient HCN cells, and provides a genuine model of autophagic cell death in apoptosis-intact cells. Novel insight into molecular mechanisms of this underappreciated form of programmed cell death should facilitate the development of therapeutic methods to cope with human diseases caused by dysregulated cell death.
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http://dx.doi.org/10.4161/auto.5.2.7641DOI Listing
February 2009

Effects of sildenafil on nigrostriatal dopamine neurons in a murine model of Parkinson's disease.

J Alzheimers Dis 2008 Sep;15(1):97-107

Department of Pharmacology, Michigan State University, East Lansing, MI 48824, USA.

The objective of this study was to determine if the phosphodiesterase 5 (PDE-5) inhibitor, sildenafil, could be used as a neuroprotective agent in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. The underlying hypothesis of these studies is that blockade of PDE-5 catabolism of cGMP will attenuate the loss of nigrostriatal dopamine (NSDA) neurons following chronic neurotoxin exposure. Chronic MPTP-treated mice were administered sildenafil using three different regimens. Animals were: 1) treated with sildenafil and then exposed to chronic MPTP; 2) treated concurrently with sildenafil and MPTP; and 3) first exposed to MPTP and subsequently treated with sildenafil. End points of neurotoxicity included dopamine (DA) and tyrosine hydroxylase (TH) concentrations in NSDA axon terminals in the striatum, and stereological cell counts of TH immunoreactive neurons in the substantia nigra. Results reveal that sildenafil did not prevent neurotoxicity produced by chronic MPTP exposure regardless of the treatment paradigms employed. On the other hand, sildenafil did not produce any deleterious effect on NSDA neuron function nor did it potentiate the neurotoxic effects of MPTP. These results suggest that sildenafil would not accelerate DA cell loss when used as a treatment for erectile dysfunction in men diagnosed with Parkinson's disease.
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http://dx.doi.org/10.3233/jad-2008-15108DOI Listing
September 2008

Autophagic death of adult hippocampal neural stem cells following insulin withdrawal.

Stem Cells 2008 Oct 24;26(10):2602-10. Epub 2008 Jul 24.

Departments of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824, USA.

Novel therapeutic approaches using stem cell transplantation to treat neurodegenerative diseases have yielded promising results. However, survival of stem cells after transplantation has been very poor in animal models, and considerable efforts have been directed at increasing the viability of engrafted stem cells. Therefore, understanding the mechanisms that regulate survival and death of neural stem cells is critical to the development of stem cell-based therapies. Hippocampal neural (HCN) stem cells derived from the adult rat brain undergo cell death following insulin withdrawal, which is associated with downregulation of antiapoptotic Bcl-2 family members. To understand the type of cell death in HCN cells following insulin withdrawal, apoptosis markers were assessed. Of note, DNA fragmentation or caspase-3 activation was not observed, but rather dying cells displayed features of autophagy, including increased expression of Beclin 1 and the type II form of light chain 3. Electron micrographs showed the dramatically increased formation of autophagic vacuoles with cytoplasmic contents. Staurosporine induced robust activation of caspase-3 and nucleosomal DNA fragmentation, suggesting that the machinery of apoptosis is intact in HCN cells despite the apparent absence of apoptosis following insulin withdrawal. Autophagic cell death was suppressed by knockdown of autophagy-related gene 7, whereas promotion of autophagy by rapamycin increased cell death. Taken together, these data demonstrate that HCN cells undergo a caspase-independent, autophagic cell death following insulin withdrawal. Understanding the mechanisms governing autophagy of adult neural stem cells may provide novel strategies to improve the survival rate of transplanted stem cells for treatment of neurodegenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.
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http://dx.doi.org/10.1634/stemcells.2008-0153DOI Listing
October 2008

Lack of D2 receptor mediated regulation of dopamine synthesis in A11 diencephalospinal neurons in male and female mice.

Brain Res 2008 Jun 19;1214:1-10. Epub 2008 Mar 19.

Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.

Dopamine (DA) neurons comprising the A11 diencephalospinal system represent the major source of DA innervation to the spinal cord. These neurons project axons throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn. Loss of DA-mediated sensorimotor function in the lumbar segment of spinal cord is implicated in the etiology of Restless Legs Syndrome (RLS), which is more prevalent in females as compared with males. The purpose of the present study was to compare the density (DA concentrations) and catabolic activity (3,4-dihydroxyphenylacetic acid; DOPAC) of A11 DA neurons innervating the lumbar spinal cord of male and female C57/BL6 mice, and to determine if there is a sexual difference in the regulation of these neurons by D2 autoreceptor-mediated mechanisms. DA concentrations in the lumbar spinal cord were higher in males, suggesting a greater A11 DA innervation as compared with females, whereas there was no sexual difference in the activity (DOPAC/DA ratio) of these DA neurons under basal conditions. Blockade of D2 receptors with raclopride caused a significant increase in the DOPAC/DA ratio in the striatum and nucleus accumbens in both males and females, but had no effect in the spinal cord. Blockade of neuronal impulse flow and DA release with gamma-butyrolactone (GBL) increased DA concentrations in the spinal cord, but this increase was not prevented by pretreatment with the D2 agonist quinelorane. These results are consistent with the conclusion that A11 diencephalospinal DA neurons in both males and females lack presynaptic synthesis modulating D2 autoreceptors.
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http://dx.doi.org/10.1016/j.brainres.2008.03.010DOI Listing
June 2008

Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism.

FASEB J 2006 Nov;20(13):2302-12

Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.

Many neurodegenerative diseases associated with functional Tau dysregulation, including Alzheimer's disease (AD) and other tauopathies, also show alpha-synuclein (alpha-Syn) pathology, a protein associated with Parkinson's disease (PD) pathology. Here we show that treatment of primary mesencephalic neurons (48 h) or subchronic treatment of wild-type (WT) mice with the Parkinsonism-inducing neurotoxin MPP+/MPTP, results in selective dose-dependent hyperphosphorylation of Tau at Ser396/404 (PHF-1-reactive Tau, p-Tau), with no changes in pSer202 but with nonspecific increases in pSer262 levels. The presence of alpha-Syn was absolutely mandatory to observe MPP+/MPTP-induced increases in p-Tau levels, since no alterations in p-Tau were seen in transfected cells not expressing alpha-Syn or in alpha-Syn-/- mice. MPP+/MPTP also induced a significant accumulation of alpha-Syn in both mesencephalic neurons and in WT mice striatum. MPTP/MPP+ lead to differential alterations in p-Tau and alpha-Syn levels in a cytoskeleton-bound, vs. a soluble, cytoskeleton-free fraction, inducing their coimmunoprecipitation in the cytoskeleton-free fraction and neuronal soma. Subchronic MPTP exposure increased sarkosyl-insoluble p-Tau in striatum of WT but not alpha-Syn-/- mice. These studies describe a novel mechanism for MPTP neurotoxicity, namely a MPTP-inducible, strictly alpha-Syn-dependent, increased formation of PHF-1-reactive Tau, suggesting convergent overlapping pathways in the genesis of clinically divergent diseases such as AD and PD.
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http://dx.doi.org/10.1096/fj.06-6092comDOI Listing
November 2006
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