Publications by authors named "David S Park"

160 Publications

Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain-of-function FHF1(FGF12) missense mutation.

Epilepsia 2021 May 13. Epub 2021 May 13.

Department of Biological Sciences, Hunter College of City University of New York, New York, New York, USA.

Objective: Fibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel-binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain-of-function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice.

Methods: The Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1 mice. Spontaneous epileptiform events in Fhf1 mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure-induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1B protein was assayed by voltage-clamp recordings of FHF-deficient mouse cardiomyocytes infected with adenoviruses expressing wild-type FHF1B or FHF1B protein.

Results: All Fhf1 mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19-20-day-old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 2-53 s after lethal seizure onset, heart rate abruptly declined from 572 ± 16 bpm to 108 ± 15 bpm, suggesting a parasympathetic surge accompanying seizures that may have contributed to SUDEP. Although ectopic overexpression of FHF1B in cardiomyocytes induced a 15-mV depolarizing shift in voltage of steady-state sodium channel inactivation and slowed the rate of channel inactivation, heart rhythm was normal in Fhf1 mice prior to seizure.

Significance: The Fhf1 missense mutation p.Arg52His induces epileptic encephalopathy with full penetrance in mice. Both Fhf1 (p.Arg52His) and Scn8a (p.Asn1768Asp) missense mutations enhance sodium channel Na 1.6 currents and induce SUDEP with bradycardia in mice, suggesting an FHF1/Na 1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy.
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http://dx.doi.org/10.1111/epi.16916DOI Listing
May 2021

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.

Acta Neuropathol 2021 05 10;141(5):725-754. Epub 2021 Mar 10.

Department of Neurobiology, Duke University, Durham, NC, USA.

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (HO) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of HO. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, HO levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; HO levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering HO. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63 lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of HO, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson's-linked neurodegeneration.
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http://dx.doi.org/10.1007/s00401-021-02285-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043881PMC
May 2021

QT interval dynamics and triggers for QT prolongation immediately following cardiac arrest.

Resuscitation 2021 May 27;162:171-179. Epub 2021 Feb 27.

Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University School of Medicine, NY, USA. Electronic address:

Background: The prolongation in QT interval typically observed following cardiac arrest is considered to be multifactorial and induced by external triggers such as hypothermia therapy and exposure to antiarrhythmic medications.

Objective: To evaluate the corrected QT interval (QTc) dynamics in the first 10 days following cardiac arrest with respect to the etiology of arrest, hypothermia and QT prolonging medications.

Methods: We enrolled 104 adult survivors of cardiac arrest, where daily ECG was available for at least 3 days. We followed their QT and QRS intervals for the first 10 days of hospitalization. We used both Bazett and Fridericia formulas to correct for heart rate. For patients with QRS < 120 we analyzed the QTc interval (n = 90) and for patients with QRS > 120 ms we analyzed the JTc (n = 104) vs. including only the narrow QRS samples (n = 89). We stratified patients by 3 groups: (1) presence of ischemic heart disease (IHD) (2) treatment with hypothermia protocol, and (3) treatment with QTc prolonging medications. Additionally, genetic information obtained during hospitalization was analyzed.

Results: QTc and JTc intervals were significantly prolonged in the first 6 days. Maximal QTc/JTc prolongation was observed in day 2 (QTcB = 497 ± 55). There were no differences in daily QTc/JTc and QRS intervals in the first 2 days post arrest between patients with or without hypothermia induction but such difference was found with QT prolonging medications. All subgroups demonstrated significantly prolonged QTc/JTc interval regardless of the presence of IHD, hypothermia protocol or QTc prolonging medication exposure. Our results were consistent for both Bazetts' and Frediricia correction and for any QRS duration. Prolongation of the JTcB beyond 382 ms after day 3 predicted sustained QTc/JTc prolongation beyond day 6 with an ROC of 0.78.

Conclusions: QTc/JTc interval is significantly and independently prolonged post SCA, regardless of known QT prolonging triggers. Normalization of the QTc post cardiac arrest should be expected only after day 6 of hospitalization. Assessment of the QTc for adjudication of the etiology of arrest or for monitoring the effect of QT prolonging medications may be unreliable.
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http://dx.doi.org/10.1016/j.resuscitation.2021.02.029DOI Listing
May 2021

Lesion Sequence and Catheter Spatial Stability Affect Lesion Quality Markers in Atrial Fibrillation Ablation.

JACC Clin Electrophysiol 2021 03 27;7(3):367-377. Epub 2021 Jan 27.

Leon H. Charney Division of Cardiology, New York University Langone Medical Center, New York University School of Medicine, New York, New York, USA.

Objectives: This study sought to analyze high-frequency catheter excursion in relation to lesion quality markers in 20 consecutive patients undergoing first-time radiofrequency (RF) ablation for paroxysmal atrial fibrillation (AF).

Background: Ablation therapy for AF requires the delivery of durable lesions. The extent to which lesion sequence, catheter spatial stability, and anatomic location influence lesion formation during RF ablation of AF is not well understood.

Methods: Three-dimensional spatial excursion of the ablation catheter sampled at 60 Hz during pre-specified pairs of RF lesions was extracted from the CARTO3 System (Biosense Webster Inc., Irvine, California) and analyzed by using custom-developed MATLAB software (MathWorks, Natick, Massachusetts) to define precise catheter spatial stability during RF ablation. Ablation parameters including bipolar electrogram amplitude reduction, impedance decline and transmurality-associated unipolar electrogram (TUE) as evidence of lesion transmurality during lesion placement were recorded and analyzed.

Results: We collected 437,760 position data points during lesion placement. Ablation catheter spatial stability and lesion formation parameters varied considerably by anatomic location. Lesions placed immediately had similar bipolar electrogram amplitude reduction, smaller impedance decline, but higher likelihood of achieving TUE compared to delayed lesions. Greater catheter spatial stability correlated with lesser impedance decline.

Conclusions: Lesion sequence, ablation catheter spatial stability, and anatomic location are important modifiers of RF lesion formation. Lesions placed immediately are more likely to exhibit TUE. Greater ablation catheter stability is associated with lesser impedance decline but greater likelihood of TUE.
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http://dx.doi.org/10.1016/j.jacep.2020.09.027DOI Listing
March 2021

Cardiac Pressure Overload Decreases ETV1 Expression in the Left Atrium, Contributing to Atrial Electrical and Structural Remodeling.

Circulation 2021 Feb 23;143(8):805-820. Epub 2020 Nov 23.

The Leon H. Charney Division of Cardiology (N.Y., J.X., D.N., D.S., X.L., E.O., A.S., D.S.P.), New York University Grossman School of Medicine.

Background: Elevated intracardiac pressure attributable to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 (ETS translocation variant 1) signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.

Methods: We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between 2 murine models of cardiac pressure overload, transverse aortic constriction banding and angiotensin II infusion, and a genetic model of cardiomyocyte-selective knockout ().

Results: Using the Cleveland Clinic biobank of human LA specimens, we found that expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the NRG1 (Neuregulin 1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between expression level and , , , and levels in human LA samples. In a similar fashion to patients with heart failure, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA sequencing datasets from transverse aortic constriction and angiotensin II-treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of , , , and and upregulation of profibrotic gene programming, which includes , and numerous collagen genes. mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA sequencing dataset from neonatal rat ventricular myocytes transduced with showed reciprocal changes.

Conclusions: ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048121DOI Listing
February 2021

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs).

Sci Rep 2020 09 30;10(1):16131. Epub 2020 Sep 30.

Institute of Medical Genetics and Applied Genomics, Tübingen University, Calwerstraße 7, 72076, Tübingen, Germany.

The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson's disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1 mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1 mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.
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http://dx.doi.org/10.1038/s41598-020-72903-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528091PMC
September 2020

Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart.

Circ Res 2020 12 23;127(12):1536-1548. Epub 2020 Sep 23.

The Leon H. Charney Division of Cardiology (D.S.P., A.S., J.S., G.R.-T., S.M., X.L., E.W.C., D.N., G.I.F.), New York University School of Medicine.

Rationale: FHFs (fibroblast growth factor homologous factors) are key regulators of sodium channel (Na) inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced Na availability in knockout () mice predisposes to abnormal excitability at the tissue level are not well defined.

Objective: Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction.

Methods And Results: mice were challenged by reducing calcium conductance (gCa) using verapamil or by reducing gap junctional conductance (Gj) using carbenoxolone or by backcrossing into a cardiomyocyte-specific Cx43 (connexin 43) heterozygous background. All conditions produced conduction block in mice, with wild-type () mice showing normal impulse propagation. To explore the ionic mechanisms of block in hearts, multicellular linear strand models incorporating FHF2-deficient Na inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced gCa or diminished Gj are very different. Enhanced Na inactivation due to FHF2 deficiency shifts dependence onto calcium current (I) to sustain electrotonic driving force, axial current flow, and action potential (AP) generation from cell-to-cell. In the setting of diminished Gj, slower charging time from upstream cells conspires with accelerated Na inactivation in mutant strands to prevent sufficient downstream cell charging for AP propagation.

Conclusions: FHF2-dependent effects on Na inactivation ensure adequate sodium current (I) reserve to safeguard against numerous threats to reliable cardiac impulse propagation.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718431PMC
December 2020

T for Two: T-Box Factors and the Functional Dichotomy of the Conduction System.

Circ Res 2020 07 16;127(3):357-359. Epub 2020 Jul 16.

From the Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371245PMC
July 2020

Myocardial infarction accelerates breast cancer via innate immune reprogramming.

Nat Med 2020 09 13;26(9):1452-1458. Epub 2020 Jul 13.

NYU Cardiovascular Research Center, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA.

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity or surgery, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6C monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6C monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.
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http://dx.doi.org/10.1038/s41591-020-0964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789095PMC
September 2020

The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin.

Nat Med 2020 06;26(6):808-809

Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University School of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41591-020-0888-2DOI Listing
June 2020

QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin.

Heart Rhythm 2020 09 12;17(9):1425-1433. Epub 2020 May 12.

Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York. Electronic address:

Background: There is no known effective therapy for patients with coronavirus disease 2019 (COVID-19). Initial reports suggesting the potential benefit of hydroxychloroquine/azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns about the potential risk of QT interval prolongation and induction of torsade de pointes (TdP).

Objective: The purpose of this study was to assess the change in corrected QT (QTc) interval and arrhythmic events in patients with COVID-19 treated with HY/AZ.

Methods: This is a retrospective study of 251 patients from 2 centers who were diagnosed with COVID-19 and treated with HY/AZ. We reviewed electrocardiographic tracings from baseline and until 3 days after the completion of therapy to determine the progression of QTc interval and the incidence of arrhythmia and mortality.

Results: The QTc interval prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc interval prolongation to >500 ms, a known marker of high risk of TdP, had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc interval of patients exhibiting extreme QTc interval prolongation was normal.

Conclusion: The combination of HY/AZ significantly prolongs the QTc interval in patients with COVID-19. This prolongation may be responsible for life-threatening arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in light of its unproven efficacy. Strict QTc interval monitoring should be performed if the regimen is given.
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http://dx.doi.org/10.1016/j.hrthm.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214283PMC
September 2020

MCL-1 maintains neuronal survival by enhancing mitochondrial integrity and bioenergetic capacity under stress conditions.

Cell Death Dis 2020 05 5;11(5):321. Epub 2020 May 5.

University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular medicine, University of Ottawa, Ottawa, ON, Canada.

Mitochondria play a crucial role in neuronal survival through efficient energy metabolism. In pathological conditions, mitochondrial stress leads to neuronal death, which is regulated by the anti-apoptotic BCL-2 family of proteins. MCL-1 is an anti-apoptotic BCL-2 protein localized to mitochondria either in the outer membrane (OM) or inner membrane (Matrix), which have distinct roles in inhibiting apoptosis and promoting bioenergetics, respectively. While the anti-apoptotic role for Mcl1 is well characterized, the protective function of MCL-1 remains poorly understood. Here, we show MCL-1 and MCL-1 prevent neuronal death through distinct mechanisms. We report that MCL-1 functions to preserve mitochondrial energy transduction and improves respiratory chain capacity by modulating mitochondrial oxygen consumption in response to mitochondrial stress. We show that MCL-1 protects neurons from stress by enhancing respiratory function, and by inhibiting mitochondrial permeability transition pore opening. Taken together, our results provide novel insight into how MCL-1 may confer neuroprotection under stress conditions involving loss of mitochondrial function.
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http://dx.doi.org/10.1038/s41419-020-2498-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200794PMC
May 2020

Rapid pacing and high-frequency jet ventilation additively improve catheter stability during atrial fibrillation ablation.

J Cardiovasc Electrophysiol 2020 07 27;31(7):1678-1686. Epub 2020 Apr 27.

The New York University Cardiac Electrophysiology Service, New York University School of Medicine, New York University Langone Health, New York, New York.

Introduction: Catheter stability during atrial fibrillation ablation is associated with higher ablation success rates. Rapid cardiac pacing and high-frequency jet ventilation (HFJV) independently improve catheter stability. Simultaneous modulation of cardiac and respiratory motion has not been previously studied. The objective of this study was to determine the effect of simultaneous heart rate and respiratory rate modulation on catheter stability.

Methods: Forty patients undergoing paroxysmal atrial fibrillation ablation received ablation lesions at 15 prespecified locations (12 left atria, 3 right atria). Patients were randomly assigned to undergo rapid atrial pacing for either the first or the second half of each lesion. Within each group, half of the patients received HFJV and the other half standard ventilation. Contact force and ablation data for all lesions were compared among the study groups. Standard deviation of contact force was the primary endpoint defined to examine contact force variability.

Results: Lesions with no pacing and standard ventilation had the greatest contact force standard deviation (5.86 ± 3.08 g), compared to lesions with pacing and standard ventilation (5.45 ± 3.28 g; P < .01) or to lesions with no pacing and HFJV (4.92 ± 3.00 g; P < .01). Lesions with both pacing and HFJV had the greatest reduction in contact force standard deviation (4.35 ± 2.81 g; P < .01), confirming an additive benefit of each maneuver. Pacing and HFJV together was also associated with a reduction in the proportion of lesions with excessive maximum contact force (P < .001).

Discussion: Rapid pacing and HFJV additively improve catheter stability. Simultaneous pacing with HFJV further improves catheter stability over pacing or HFJV alone to optimize ablation lesions.
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http://dx.doi.org/10.1111/jce.14507DOI Listing
July 2020

A functionalized hydroxydopamine quinone links thiol modification to neuronal cell death.

Redox Biol 2020 01 9;28:101377. Epub 2019 Nov 9.

Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie Private, Ottawa, ON, K1N 6N5, Canada. Electronic address:

Recent findings suggest that dopamine oxidation contributes to the development of Parkinson's disease (PD); however, the mechanistic details remain elusive. Here, we compare 6-hydroxydopamine (6-OHDA), a product of dopamine oxidation that commonly induces dopaminergic neurodegeneration in laboratory animals, with a synthetic alkyne-functionalized 6-OHDA variant. This synthetic molecule provides insights into the reactivity of quinone and neuromelanin formation. Employing Huisgen cycloaddition chemistry (or "click chemistry") and fluorescence imaging, we found that reactive 6-OHDA p-quinones cause widespread protein modification in isolated proteins, lysates and cells. We identified cysteine thiols as the target site and investigated the impact of proteome modification by quinones on cell viability. Mass spectrometry following cycloaddition chemistry produced a large number of 6-OHDA modified targets including proteins involved in redox regulation. Functional in vitro assays demonstrated that 6-OHDA inactivates protein disulfide isomerase (PDI), which is a central player in protein folding and redox homeostasis. Our study links dopamine oxidation to protein modification and protein folding in dopaminergic neurons and the PD model.
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http://dx.doi.org/10.1016/j.redox.2019.101377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880099PMC
January 2020

alleles modulate inflammation during microbial infection of mice in a sex-dependent manner.

Sci Transl Med 2019 09;11(511)

Program in Neuroscience, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

Variants in the leucine-rich repeat kinase-2 () gene are associated with Parkinson's disease, leprosy, and Crohn's disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested this hypothesis in two ways. First, adult mice were intravenously inoculated with , resulting in sepsis. Second, newborn mouse pups were intranasally infected with reovirus (serotype 3 Dearing), which induced encephalitis. In both mouse models, wild-type Lrrk2 expression was protective and showed a sex effect, with female Lrrk2-deficient animals not controlling infection as well as males. Mice expressing Lrrk2 carrying the Parkinson's disease-linked p.G2019S mutation controlled infection better, with reduced bacterial growth and longer animal survival during sepsis. This gain-of-function effect conferred by the p.G2019S mutation was mediated by myeloid cells and was abolished in animals expressing a kinase-dead Lrrk2 variant, p.D1994S. Mouse pups with reovirus-induced encephalitis that expressed the p.G2019S Lrrk2 mutation showed increased mortality despite lower viral titers. The p.G2019S mutant Lrrk2 augmented immune cell chemotaxis and generated more reactive oxygen species during virulent infection. Reovirus-infected brains from mice expressing the p.G2019S mutant Lrrk2 contained higher concentrations of α-synuclein. Animals expressing one or two p.D1994S alleles showed lower mortality from reovirus-induced encephalitis. Thus, alleles may alter the course of microbial infections by modulating inflammation, and this may be dependent on the sex and genotype of the host as well as the type of pathogen.
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http://dx.doi.org/10.1126/scitranslmed.aas9292DOI Listing
September 2019

Utilization of a Radiation Safety Time-Out Reduces Radiation Exposure During Electrophysiology Procedures.

JACC Clin Electrophysiol 2019 05 30;5(5):626-634. Epub 2019 Jan 30.

New York University Cardiac Electrophysiology Service, New York University School of Medicine, New York University Langone Medical Center, New York, New York.

Objectives: This study sought to determine whether a radiation safety time-out reduces radiation exposure in electrophysiology procedures.

Background: Time-outs are integral to improving quality and safety. The authors hypothesized that a radiation safety time-out would reduce radiation exposure levels for patients and the health care team members.

Methods: The study was performed at the New York University Langone Health Electrophysiology Lab. Baseline data were collected for 6 months prior to the time-out. On implementation of the time-out, data were collected prospectively with analyses to be performed every 3 months. The primary endpoint was dose area product. The secondary endpoints included reference point dose, fluoroscopy time, use of additional shielding, and use of alternative imaging such as intracardiac and intravascular ultrasound.

Results: A total of 1,040 patient cases were included. The median dose area product prior to time-out was 18.7 Gy∙cm, and the median during the time-out was 14.7 Gy∙cm, representing a 21% reduction (p = 0.007). The median reference point dose prior to time-out was 163 mGy, and during the time-out was 122 mGy (p = 0.011). The use of sterile disposable protective shields and ultrasound imaging for access increased significantly during the time-out.

Conclusions: A radiation safety time-out significantly reduces radiation exposure in electrophysiology procedures. Electrophysiology laboratories, as well as other areas of cardiovascular medicine using fluoroscopy, should strongly consider the use of radiation safety time-outs to reduce radiation exposure and improve safety.
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http://dx.doi.org/10.1016/j.jacep.2018.12.002DOI Listing
May 2019

The pro-death role of Cited2 in stroke is regulated by E2F1/4 transcription factors.

J Biol Chem 2019 05 9;294(21):8617-8629. Epub 2019 Apr 9.

University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Hotchkiss Brain Institute, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada. Electronic address:

We previously reported that the cell cycle-related cyclin-dependent kinase 4-retinoblastoma (RB) transcriptional corepressor pathway is essential for stroke-induced cell death both and However, how this signaling pathway induces cell death is unclear. Previously, we found that the cyclin-dependent kinase 4 pathway activates the pro-apoptotic transcriptional co-regulator Cited2 after DNA damage. In the present study, we report that Cited2 protein expression is also dramatically increased following stroke/ischemic insult. Critically, utilizing conditional knockout mice, we show that Cited2 is required for neuronal cell death, both in culture and in mice after ischemic insult. Importantly, determining the mechanism by which Cited2 levels are regulated, we found that E2F transcription factor (E2F) family members participate in Cited2 regulation. First, E2F1 expression induced transcription, and E2F1 deficiency reduced expression. Moreover, determining the potential E2F-binding regions on the gene regulatory sequence by ChIP analysis, we provide evidence that E2F1/4 proteins bind to this DNA region. A luciferase reporter assay to probe the functional outcomes of this interaction revealed that E2F1 activates and E2F4 inhibits transcription. Moreover, we identified the functional binding motif for E2F1 in the gene promoter by demonstrating that mutation of this site dramatically reduces E2F1-mediated transcription. Finally, E2F1 and E2F4 regulated expression in neurons after stroke-related insults. Taken together, these results indicate that the E2F- regulatory pathway is critically involved in stroke injury.
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http://dx.doi.org/10.1074/jbc.RA119.007941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544850PMC
May 2019

Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer's disease neurons.

Aging Cell 2019 06 21;18(3):e12924. Epub 2019 Feb 21.

Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.

Mitochondrial dysfunction is implicated in most neurodegenerative diseases, including Alzheimer's disease (AD). We here combined experimental and computational approaches to investigate mitochondrial health and bioenergetic function in neurons from a double transgenic animal model of AD (PS2APP/B6.152H). Experiments in primary cortical neurons demonstrated that AD neurons had reduced mitochondrial respiratory capacity. Interestingly, the computational model predicted that this mitochondrial bioenergetic phenotype could not be explained by any defect in the mitochondrial respiratory chain (RC), but could be closely resembled by a simulated impairment in the mitochondrial NADH flux. Further computational analysis predicted that such an impairment would reduce levels of mitochondrial NADH, both in the resting state and following pharmacological manipulation of the RC. To validate these predictions, we utilized fluorescence lifetime imaging microscopy (FLIM) and autofluorescence imaging and confirmed that transgenic AD neurons had reduced mitochondrial NAD(P)H levels at rest, and impaired power of mitochondrial NAD(P)H production. Of note, FLIM measurements also highlighted reduced cytosolic NAD(P)H in these cells, and extracellular acidification experiments showed an impaired glycolytic flux. The impaired glycolytic flux was identified to be responsible for the observed mitochondrial hypometabolism, since bypassing glycolysis with pyruvate restored mitochondrial health. This study highlights the benefits of a systems biology approach when investigating complex, nonintuitive molecular processes such as mitochondrial bioenergetics, and indicates that primary cortical neurons from a transgenic AD model have reduced glycolytic flux, leading to reduced cytosolic and mitochondrial NAD(P)H and reduced mitochondrial respiratory capacity.
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http://dx.doi.org/10.1111/acel.12924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516149PMC
June 2019

DJ-1 modulates the unfolded protein response and cell death via upregulation of ATF4 following ER stress.

Cell Death Dis 2019 02 12;10(2):135. Epub 2019 Feb 12.

Department of Clinical Neurosciences, and Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.

The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress is a feature of many neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease (PD). Although the vast majority of PD is sporadic, mutations in a number of genes including PARK7 which encodes the protein DJ-1 have been linked to early-onset, familial PD. In this regard, both PD of sporadic and genetic origins exhibit markers of ER stress-induced UPR. However, the relationship between pathogenic mutations in PARK7 and ER stress-induced UPR in PD pathogenesis remains unclear. In most contexts, DJ-1 has been shown to protect against neuronal injury. However, we find that DJ-1 deficiency ameliorates death in the context of acute ER stress in vitro and in vivo. DJ-1 loss decreases protein and transcript levels of ATF4, a transcription factor critical to the ER response and reduces the levels of CHOP and BiP, its downstream effectors. The converse is observed with DJ-1 over-expression. Importantly, we find that over-expression of wild-type and PD-associated mutant form of PARK7, enhances ER stress-induced neuronal death by regulating ATF4 transcription and translation. Our results demonstrate a previously unreported role for wild-type and mutant DJ-1 in the regulation of UPR and provides a potential link to PD pathogenesis.
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http://dx.doi.org/10.1038/s41419-019-1354-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372623PMC
February 2019

Year in Review in Cardiac Electrophysiology.

Circ Arrhythm Electrophysiol 2019 02;12(2):e007142

Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, MN (M.M., S.K.).

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http://dx.doi.org/10.1161/CIRCEP.118.007142DOI Listing
February 2019

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP

J Neurochem 2019 08 2;150(3):312-329. Epub 2019 Apr 2.

Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, South Korea.

Loss of function mutations in the PTEN-induced putative kinase 1 (Pink1) gene have been linked with an autosomal recessive familial form of early onset Parkinson's disease (PD). However, the underlying mechanism(s) responsible for degeneration remains elusive. Presently, using co-immunoprecipitation in HEK (Human embryonic kidney) 293 cells, we show that Pink1 endogenously interacts with FK506-binding protein 51 (FKBP51 or FKBP5), FKBP5 and directly phosphorylates FKBP5 at Serine in an in vitro kinase assay. Both FKBP5 and Pink1 have been previously associated with protein kinase B (AKT) regulation. We provide evidence using primary cortical cultured neurons from Pink1-deficient mice that Pink1 increases AKT phosphorylation at Serine 473 (Ser473) challenged by 1-methyl-4-phenylpyridinium (MPP ) and that over-expression of FKBP5 using an adeno-associated virus delivery system negatively regulates AKT phosphorylation at Ser473 in murine-cultured cortical neurons. Interestingly, FKBP5 over-expression promotes death in response to MPP in the absence of Pink1. Conversely, shRNA-mediated knockdown of FKBP5 in cultured cortical neurons is protective and this effect is reversed with inhibition of AKT signaling. In addition, shRNA down-regulation of PH domain leucine-rich repeat protein phosphatase (PHLPP) in Pink1 WT neurons increases neuronal survival, while down-regulation of PHLPP in Pink1 KO rescues neuronal death in response to MPP . Finally, using co-immunoprecipitation, we show that FKBP5 interacts with the kinase AKT and phosphatase PHLPP. This interaction is increased in the absence of Pink1, both in Mouse Embryonic Fibroblasts (MEF) and in mouse brain tissue. Expression of kinase dead Pink1 (K219M) enhances FKBP5 interaction with both AKT and PHLPP. Overall, our results suggest a testable model by which Pink1 could regulate AKT through phosphorylation of FKBP5 and interaction of AKT with PHLPP. Our results suggest a potential mechanism by which PINK1-FKBP5 pathway contributes to neuronal death in PD. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
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http://dx.doi.org/10.1111/jnc.14683DOI Listing
August 2019

Pacing Mediated Heart Rate Acceleration Improves Catheter Stability and Enhances Markers for Lesion Delivery in Human Atria During Atrial Fibrillation Ablation.

JACC Clin Electrophysiol 2018 04 1;4(4):483-490. Epub 2018 Mar 1.

New York University Cardiac Electrophysiology Service, New York University School of Medicine, New York University Langone Medical Center, New York, New York.

Objectives: This study sought to investigate the effect of pacing mediated heart rate modulation on catheter-tissue contact and impedance reduction during radiofrequency ablation in human atria during atrial fibrillation (AF) ablation.

Background: In AF ablation, improved catheter-tissue contact enhances lesion quality and acute pulmonary vein isolation rates. Previous studies demonstrate that catheter-tissue contact varies with ventricular contraction. The authors investigated the impact of modulating heart rate on the consistency of catheter-tissue contact and its effect on lesion quality.

Methods: Twenty patients undergoing paroxysmal AF ablation received ablation lesions at 15 pre-specified locations (12 left atria, 3 right atria). Patients were assigned randomly to undergo rapid atrial pacing for either the first half or the second half of each lesion. Contact force and ablation data with and without pacing were compared for each of the 300 ablation lesions.

Results: Compared with lesion delivery without pacing, pacing resulted in reduced contact force variability, as measured by contact force SD, range, maximum, minimum, and time within the pre-specified goal contact force range (p < 0.05). There was no difference in the mean contact force or force-time integral. Reduced contact force variability was associated with a 30% greater decrease in tissue impedance during ablation (p < 0.001).

Conclusions: Pacing induced heart rate acceleration reduces catheter-tissue contact variability, increases the probability of achieving pre-specified catheter-tissue contact endpoints, and enhances impedance reduction during ablation. Modulating heart rate to improve catheter-tissue contact offers a new approach to optimize lesion quality in AF ablation. (The Physiological Effects of Pacing on Catheter Ablation Procedures to Treat Atrial Fibrillation [PEP AF]; NCT02766712).
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http://dx.doi.org/10.1016/j.jacep.2017.12.017DOI Listing
April 2018

Year in Review in Cardiac Electrophysiology.

Circ Arrhythm Electrophysiol 2018 07;11(7):e006648

Cardiovascular Medicine, School of Medicine, Stanford University, CA (M.N.V., P.J.W.).

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http://dx.doi.org/10.1161/CIRCEP.118.006648DOI Listing
July 2018

ETV1 activates a rapid conduction transcriptional program in rodent and human cardiomyocytes.

Sci Rep 2018 07 2;8(1):9944. Epub 2018 Jul 2.

Leon H. Charney Division of Cardiology, New York University Langone Health, New York, New York, 10016, USA.

Rapid impulse propagation is a defining attribute of the pectinated atrial myocardium and His-Purkinje system (HPS) that safeguards against atrial and ventricular arrhythmias, conduction block, and myocardial dyssynchrony. The complex transcriptional circuitry that dictates rapid conduction remains incompletely understood. Here, we demonstrate that ETV1 (ER81)-dependent gene networks dictate the unique electrophysiological characteristics of atrial and His-Purkinje myocytes. Cardiomyocyte-specific deletion of ETV1 results in cardiac conduction abnormalities, decreased expression of rapid conduction genes (Nkx2-5, Gja5, and Scn5a), HPS hypoplasia, and ventricularization of the unique sodium channel properties that define Purkinje and atrial myocytes in the adult heart. Forced expression of ETV1 in postnatal ventricular myocytes (VMs) reveals that ETV1 promotes a HPS gene signature while diminishing ventricular and nodal gene networks. Remarkably, ETV1 induction in human induced pluripotent stem cell-derived cardiomyocytes increases rapid conduction gene expression and inward sodium currents, converting them towards a HPS phenotype. Our data identify a cardiomyocyte-autonomous, ETV1-dependent pathway that is responsible for specification of rapid conduction zones in the heart and demonstrate that ETV1 is sufficient to promote a HPS transcriptional and functional program upon VMs.
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http://dx.doi.org/10.1038/s41598-018-28239-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028599PMC
July 2018

Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson's disease.

Proc Natl Acad Sci U S A 2018 05 14;115(22):E5164-E5173. Epub 2018 May 14.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;

Leucine-rich repeat kinase 2 () has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively. Lrrk2 loss results in the opposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its proteasomal degradation. Finally, we show that Wave2 also mediates Lrrk2G2019S-induced dopaminergic neuronal death in both macrophage-midbrain cocultures and in vivo. Taken together, a LRRK2-WAVE2 pathway, which modulates the phagocytic response in mice and human leukocytes, may define an important role for altered immune function in PD.
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http://dx.doi.org/10.1073/pnas.1718946115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984500PMC
May 2018

Comparative analysis of Parkinson's disease-associated genes in mice reveals altered survival and bioenergetics of Parkin-deficient dopamine neurons.

J Biol Chem 2018 06 26;293(25):9580-9593. Epub 2018 Apr 26.

From the Departments of Pharmacology and Physiology and

Many mutations in genes encoding proteins such as Parkin, PTEN-induced putative kinase 1 (PINK1), protein deglycase DJ-1 (DJ-1 or PARK7), leucine-rich repeat kinase 2 (LRRK2), and α-synuclein have been linked to familial forms of Parkinson's disease (PD). The consequences of these mutations, such as altered mitochondrial function and pathological protein aggregation, are starting to be better understood. However, little is known about the mechanisms explaining why alterations in such diverse cellular processes lead to the selective loss of dopamine (DA) neurons in the substantia nigra (SNc) in the brain of individuals with PD. Recent work has shown that one of the reasons for the high vulnerability of SNc DA neurons is their high basal rate of mitochondrial oxidative phosphorylation (OXPHOS), resulting from their highly complex axonal arborization. Here, we examined whether axonal growth and basal mitochondrial function are altered in SNc DA neurons from Parkin-, Pink1-, or DJ-1-KO mice. We provide evidence for increased basal OXPHOS in Parkin-KO DA neurons and for reduced survival of DA neurons that have a complex axonal arbor. The surviving smaller neurons exhibited reduced vulnerability to the DA neurotoxin and mitochondrial complex I inhibitor MPP+, and this reduction was associated with reduced expression of the DA transporter. Finally, we found that glial cells play a role in the reduced resilience of DA neurons in these mice and that WT Parkin overexpression rescues this phenotype. Our results provide critical insights into the complex relationship between mitochondrial function, axonal growth, and genetic risk factors for PD.
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http://dx.doi.org/10.1074/jbc.RA117.000499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016451PMC
June 2018

SCN5A: the greatest HITS collection.

J Clin Invest 2018 03 19;128(3):913-915. Epub 2018 Feb 19.

Heart failure (HF) has been referred to as the cardiovascular epidemic of our time. Understanding the molecular determinants of HF disease progression and mortality risk is of utmost importance. In this issue of the JCI, Zhang et al. uncover an important link between clinical HF mortality risk and a common variant that regulates SCN5A expression through microRNA-dependent (miR-dependent)mechanisms. They also demonstrate that haploinsufficiency of SCN5A is associated with increased accumulation of reactive oxygen species (ROS) in a genetically engineered murine model. Their data suggest that even modest depression of SCN5A expression may promote pathologic cardiac remodeling and progression of HF.
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http://dx.doi.org/10.1172/JCI99927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824860PMC
March 2018

Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases.

Cell Death Differ 2018 03 11;25(3):542-572. Epub 2017 Dec 11.

Dpto. de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049, Madrid, Spain.

Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium ( www.cebiond.org ), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer's, Parkinson's, and Huntington's diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field.
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http://dx.doi.org/10.1038/s41418-017-0020-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864235PMC
March 2018

PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress.

Nat Commun 2017 11 9;8(1):1399. Epub 2017 Nov 9.

University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada, K1H 8M5.

Mutations in PTEN-induced kinase 1 (PINK1) result in a recessive familial form of Parkinson's disease (PD). PINK1 loss is associated with mitochondrial Ca mishandling, mitochondrial dysfunction, as well as increased neuronal vulnerability. Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro. Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. Expression of LETM1-T192E but not LETM1-wild type (WT) rescues mitochondrial calcium mishandling in PINK1-deficient neurons. Expression of both LETM1-WT and LETM1-T192E protects neurons against MPP-MPTP-induced neuronal death in PINK1 WT neurons, whereas only LETM1-T192E protects neurons under conditions of PINK1 loss. Our findings delineate a mechanism by which PINK1 regulates mitochondrial Ca level through LETM1 and suggest a model by which PINK1 loss leads to deficient phosphorylation of LETM1 and impaired mitochondrial Ca transport..
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http://dx.doi.org/10.1038/s41467-017-01435-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680261PMC
November 2017

Development and Function of the Cardiac Conduction System in Health and Disease.

J Cardiovasc Dev Dis 2017 7;4(2). Epub 2017 Jun 7.

Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.

The generation and propagation of the cardiac impulse is the central function of the cardiac conduction system (CCS). Impulse initiation occurs in nodal tissues that have high levels of automaticity, but slow conduction properties. Rapid impulse propagation is a feature of the ventricular conduction system, which is essential for synchronized contraction of the ventricular chambers. When functioning properly, the CCS produces ~2.4 billion heartbeats during a human lifetime and orchestrates the flow of cardiac impulses, designed to maximize cardiac output. Abnormal impulse initiation or propagation can result in brady- and tachy-arrhythmias, producing an array of symptoms, including syncope, heart failure or sudden cardiac death. Underlying the functional diversity of the CCS are gene regulatory networks that direct cell fate towards a nodal or a fast conduction gene program. In this review, we will discuss our current understanding of the transcriptional networks that dictate the components of the CCS, the growth factor-dependent signaling pathways that orchestrate some of these transcriptional hierarchies and the effect of aberrant transcription factor expression on mammalian conduction disease.
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http://dx.doi.org/10.3390/jcdd4020007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663314PMC
June 2017