Publications by authors named "Katharine M von Herrmann"

9 Publications

  • Page 1 of 1

Lifestyle Factors and Parkinson's Disease Risk in a Rural New England Case-Control Study.

Parkinsons Dis 2021 2;2021:5541760. Epub 2021 Jul 2.

Geisel School of Medicine at Dartmouth, Rubin Building, Lebanon, NH, USA.

Introduction: Parkinson's disease (PD) is an age-related neurodegenerative disease likely caused by complex interactions between genetic and environmental risk factors. Exposure to pesticides, toxic metals, solvents, and history of traumatic brain injury have been implicated as environmental risk factors for PD, underscoring the importance of identifying risk factors associated with PD across different communities.

Methods: We conducted a questionnaire-based case-control study in a rural area on the New Hampshire/Vermont border, enrolling PD patients and age- and sex-matched controls from the general population between 2017 and 2020. We assessed frequent participation in a variety of recreational and occupational activities and surveyed potential chemical exposures.

Results: Suffering from "head trauma or a concussion" prior to diagnosis was associated with a fourfold increased risk of PD. Adjustment for head trauma negated any risk of participation in "strenuous athletic activities." We observed a 2.7-fold increased risk of PD associated with activities involving lead (adjusted =0.038).

Conclusion: Implicating these factors in PD risk favors public health efforts in exposure mitigation while also motivating future work mechanisms and intervention opportunities.
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http://dx.doi.org/10.1155/2021/5541760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270694PMC
July 2021

Bbc3 loss enhances survival and protein clearance in neurons exposed to the organophosphate pesticide chlorpyrifos.

Toxicol Sci 2021 Jul 21. Epub 2021 Jul 21.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH.

Exposure to environmental toxicants can increase the risk of developing age-related neurodegenerative disorders. Exposure to the widely used organophosphate pesticide chlorpyrifos (CPF) is associated with increased risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD), but the cellular mechanisms underlying CPF toxicity in neurons are not completely understood. We evaluated CPF toxicity in mouse primary cortical neuronal cultures, using RNA-Seq to identify cellular pathways modulated by CPF. CPF exposure altered the expression of genes associated with intrinsic apoptosis, significantly elevating expression of the pro-apoptotic mediator Bbc3/Puma. Bbc3 loss attenuated CPF driven neurotoxicity, induction of other intrinsic apoptosis regulatory genes including Trp53 and Pmaip1 (encoding the NOXA protein), and cleavage of apoptosis executors caspase 3 and PARP. CPF exposure was associated with enhanced expression of ER stress-related genes and proteins and the accumulation of high molecular weight protein species in primary neuronal cultures. No evidence of alterations in the ubiquitin-proteosome system were observed, however, autophagy-related proteins were upregulated in CPF-treated Bbc3-/- neuronal cultures compared with identically exposed WT cultures. Elevated autophagy-related protein expression in Bbc3-/- neuronal cultures was associated with a reduction in CPF-induced high molecular weight alpha-synuclein and tau immunoreactive protein aggregates. Studies indicate that Bbc3-/- neuronal cultures enhance the ER stress response and upregulate protein clearance mechanisms as a component of resistance to CPF-mediated toxicity.
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http://dx.doi.org/10.1093/toxsci/kfab090DOI Listing
July 2021

Plasma-borne indicators of inflammasome activity in Parkinson's disease patients.

NPJ Parkinsons Dis 2021 Jan 4;7(1). Epub 2021 Jan 4.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related "speck" formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.
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http://dx.doi.org/10.1038/s41531-020-00147-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782812PMC
January 2021

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice.

J Neuroinflammation 2020 Jul 17;17(1):213. Epub 2020 Jul 17.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, 1 Rope Ferry Road, Hanover, NH, 03755, USA.

Background: An association between neuroinflammation and age-related neurologic disorders has been established but the molecular mechanisms and cell types involved have not been thoroughly characterized. Activity of the proinflammatory NLRP3 inflammasome is implicated in Alzheimer's and Parkinson's disease and our recent studies in patients suggest that dopaminergic neurons within the degenerating mesencephalon express NLRP3 throughout the progression of PD. Here, we directly test the impact of enhanced inflammasome activity in mesencephalic neurons by characterizing motor function, tissue integrity, and neuroinflammation in aging mice harboring hyperactivating mutations within the endogenous murine Nlrp3 locus, enabled only in cells expressing the dopaminergic neuron-specific Slc6a3 promoter.

Methods: We compared mice harboring inducible alleles encoding the cryopyrin-associated periodic syndrome activating mutations Nlrp3 and Nlrp3 inserted into the endogenous mouse Nlrp3 locus. Tissue specific expression was driven by breeding these animals with mice expressing Cre recombinase under the control of the dopaminergic neuron-specific Slc6a3 promoter. The experimental mice, designed to express hyperactive NLRP3 only when the endogenous mouse Nlrp3 promotor is active in dopaminergic neurons, were analyzed throughout 18 months of aging using longitudinal motor function assessments. Biochemical and histologic analyses of mesencephalic tissues were conducted in 1- and 18-month-old animals.

Results: We observed progressive and significant deficits in motor function in animals expressing Nlrp3, compared with animals expressing Nlrp3 and Nlrp3. Age-dependent neuroinflammatory changes in the mesencephalon were noted in all animals. Analysis of GFAP-immunoreactive astrocytes in the substantia nigra revealed a significant increase in astrocyte number in animals expressing Nlrp3 compared with Nlrp3 and Nlrp3. Further analysis of Nlrp3 striatal tissues indicated genotype specific gliosis, elevated Il1b expression, and both morphologic and gene expression indicators of proinflammatory A1 astrocytes.

Conclusions: Dopaminergic neurons have the potential to accumulate NLRP3 inflammasome activators with age, including reactive oxygen species, dopamine metabolites, and misfolded proteins. Results indicate the Nlrp3 locus is active in dopaminergic neurons in aging mice, and that the hyperactive Nlrp3 allele can drive neuroinflammatory changes in association with progressive behavioral deficits. Findings suggest neuronal NLRP3 inflammasome activity may contribute to neuroinflammation observed during normal aging and the progression of neurologic disorders.
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http://dx.doi.org/10.1186/s12974-020-01866-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368774PMC
July 2020

expression in mesencephalic neurons and characterization of a rare polymorphism associated with decreased risk of Parkinson's disease.

NPJ Parkinsons Dis 2018 15;4:24. Epub 2018 Aug 15.

1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth and Dartmouth-Hitchcock Medical Center, Lebanon, NH USA.

Neuroinflammation is a well-characterized pathophysiology occurring in association with the progression of Parkinson's disease. Characterizing the cellular and molecular basis of neuroinflammation is critical to understanding its impact on the incidence and progression of PD and other neurologic disorders. Inflammasomes are intracellular pro-inflammatory pattern-recognition receptors capable of initiating and propagating inflammation. These cellular complexes are well characterized in the innate immune system and activity of the NLRP3 inflammasome has been reported in microglia. NLRP3 inflammasome activity has been associated with Alzheimer's disease, and recent reports, from our laboratory and others, indicate that is required for neuroinflammation and nigral cell loss in animal models of PD. has not yet been characterized in PD patients. Here we characterize in PD using immunohistologic and genetic approaches. Histologic studies revealed elevated expression in mesencephalic neurons of PD patients. Analysis of exome sequencing data for genetic variation of identified multiple single-nucleotide polymorphisms (SNPs) including rs7525979 that was associated with a significantly reduced risk of developing PD. Mechanistic studies conducted in HEK293 cells indicated that the synonymous SNP, rs7525979, alters the efficiency of translation impacting NLRP3 protein stability, ubiquitination state, and solubility. These data provide evidence that dopaminergic neurons are a cell-of-origin for inflammasome activity in PD and are consistent with recent animal studies, suggesting that inflammasome activity may impact the progression of PD.
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http://dx.doi.org/10.1038/s41531-018-0061-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093937PMC
August 2018

Editor's Highlight: Nlrp3 Is Required for Inflammatory Changes and Nigral Cell Loss Resulting From Chronic Intragastric Rotenone Exposure in Mice.

Toxicol Sci 2017 09;159(1):64-75

Department of Molecular and Systems Biology.

Complex interactions between genetic and environmental factors are widely believed to underlie the incidence and progression of Parkinson's disease (PD). Rotenone is a naturally occurring metabolic toxin employed as an insecticide and piscicide identified as a risk factor for the development of PD in agricultural workers. The Nlrp3 inflammasome is an intracellular mediator that can initiate an inflammatory cascade in response to cellular stress. Reports by others indicating that NLRP3 expression was detectable in tissues obtained from Alzheimer's disease patients and that the PD-associated protein α-synuclein could activate inflammasomes in cultured glial cells, prompted us to test the prediction that Nlrp3 was required for the development of Parkinson's-like changes resulting from rotenone exposure in mice. We exposed wild type and Nlrp3-/- mice to chronic low doses of intragastric rotenone and conducted longitudinal behavioral and serum cytokine analysis followed by evaluation of neuroinflammatory and neurodegenerative endpoints in brain tissues. We observed progressive rotenone-dependent changes in serum cytokine levels and circulating leukocytes in wild type mice not observed in Nlrp3-/- mice. Analysis of brain tissues revealed Nlrp3-dependent neuroinflammation and nigral cell loss in mice exposed to rotenone as compared with mice exposed to vehicle alone. Together, our findings provide compelling evidence of a role for Nlrp3 in nigral degeneration and neuroinflammation resulting from systemic rotenone exposure and suggest that the suppression of NLRP3 activity may be a rational neuroprotective strategy for toxin-associated PD.
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http://dx.doi.org/10.1093/toxsci/kfx117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837210PMC
September 2017

Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration.

PLoS One 2016 1;11(12):e0167077. Epub 2016 Dec 1.

Department of Neurology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.

Introduction And Objective: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers.

Methods: SMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90.

Results: Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO.

Conclusion: This study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167077PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132001PMC
June 2017

5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients.

Nat Commun 2016 11 25;7:13177. Epub 2016 Nov 25.

Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.

Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome. Here, we resolve genome-wide 5-methylcytosine and 5-hydroxymethylcytosine in glioblastoma through parallel processing of DNA with bisulfite and oxidative bisulfite treatments. We apply a statistical algorithm to estimate 5-methylcytosine, 5-hydroxymethylcytosine and unmethylated proportions from methylation array data. We show that 5-hydroxymethylcytosine is depleted in glioblastoma compared with prefrontal cortex tissue. In addition, the genomic localization of 5-hydroxymethylcytosine in glioblastoma is associated with features of dynamic cell-identity regulation such as tissue-specific transcription and super-enhancers. Annotation of 5-hydroxymethylcytosine genomic distribution reveal significant associations with RNA regulatory processes, immune function, stem cell maintenance and binding sites of transcription factors that drive cellular proliferation. In addition, model-based clustering results indicate that patients with low-5-hydroxymethylcytosine patterns have significantly poorer overall survival. Our results demonstrate that 5-hydroxymethylcytosine patterns are strongly related with transcription, localizes to disease-critical genes and are associated with patient prognosis.
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http://dx.doi.org/10.1038/ncomms13177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133638PMC
November 2016

SMN Protein Can Be Reliably Measured in Whole Blood with an Electrochemiluminescence (ECL) Immunoassay: Implications for Clinical Trials.

PLoS One 2016 8;11(3):e0150640. Epub 2016 Mar 8.

Spinal Muscular Atrophy Foundation, New York, New York, United States of America.

Spinal muscular atrophy (SMA) is caused by defects in the survival motor neuron 1 (SMN1) gene that encodes survival motor neuron (SMN) protein. The majority of therapeutic approaches currently in clinical development for SMA aim to increase SMN protein expression and there is a need for sensitive methods able to quantify increases in SMN protein levels in accessible tissues. We have developed a sensitive electrochemiluminescence (ECL)-based immunoassay for measuring SMN protein in whole blood with a minimum volume requirement of 5μL. The SMN-ECL immunoassay enables accurate measurement of SMN in whole blood and other tissues. Using the assay, we measured SMN protein in whole blood from SMA patients and healthy controls and found that SMN protein levels were associated with SMN2 copy number and were greater in SMA patients with 4 copies, relative to those with 2 and 3 copies. SMN protein levels did not vary significantly in healthy individuals over a four-week period and were not affected by circadian rhythms. Almost half of the SMN protein was found in platelets. We show that SMN protein levels in C/C-allele mice, which model a mild form of SMA, were high in neonatal stage, decreased in the first few weeks after birth, and then remained stable throughout the adult stage. Importantly, SMN protein levels in the CNS correlated with SMN levels measured in whole blood of the C/C-allele mice. These findings have implications for the measurement of SMN protein induction in whole blood in response to SMN-upregulating therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150640PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783032PMC
August 2016
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