Schwarzschild, Michael

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Schwarzschild, Michael

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Schwarzschild

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Michael

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Schwarzschild, Michael

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Red hair, MC1R variants, and risk for Parkinson's disease – a meta‐analysis
(John Wiley and Sons Inc., 2017) Chen, Xiqun; Feng, Danielle; Schwarzschild, Michael; Gao, Xiang
Abstract Several studies have been conducted with mixed results since our initial report of increased Parkinson's disease risk in individuals with red hair and/or red hair‐associated p.R151C variant of the MC1R gene, both of which confer high melanoma risk. We performed a meta‐analysis of six publications on red hair, MC1R, and Parkinson's disease. We found that red hair (pooled odds ratios = 1.68, 95% confidence intervals: 1.07, 2.64) and p.R151C (pooled odds ratios = 1.10, 95% confidence intervals: 1.00, 1.21), but not p.R160W, were associated with greater risk for Parkinson's disease. Our results support potential roles of pigmentation and its key regulator MC1R in the pathogenesis of Parkinson's disease.
Bimolecular Fluorescence Complementation of Alpha-synuclein Demonstrates its Oligomerization with Dopaminergic Phenotype in Mice
(Elsevier, 2018) Cai, Waijiao; Feng, Danielle; Schwarzschild, Michael; McLean, Pamela J.; Chen, Xiqun
Alpha-synuclein (αSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species. We report here neurochemical, neuropathological and behavioral characterization of BiFC of αSyn in mice. Overexpression and oligomerization of αSyn through BiFC is detected by conjugated fluorescence. Reduced striatal dopamine and loss of nigral dopaminergic neurons are accompanied neuroinflammation and abnormal motor activities. Our mouse model may provide a valuable tool to study the role of αSyn in PD and to explore therapeutic approaches.
Particulate matter and risk of parkinson disease in a large prospective study of women
(BioMed Central, 2014) Palacios, Natalia; Fitzgerald, Kathryn C.; Hart, Jaime; Weisskopf, Marc; Schwarzschild, Michael; Ascherio, Alberto; Laden, Francine
Background: Exposure to air pollution has been implicated in a number of adverse health outcomes and the effect of particulate matter (PM) on the brain is beginning to be recognized. Yet, no prospective study has examined the association between PM and risk of Parkinson Disease. Thus, our goal was assess if exposure to particulate matter air pollution is related to risk of Parkinson’s disease (PD) in the Nurses’ Health Study (NHS), a large prospective cohort of women. Methods: Cumulative average exposure to different size fractions of PM up to 2 years before the onset of PD, was estimated using a spatio-temporal model by linking each individual’s places of residence throughout the study with location-specific air pollution levels. We prospectively followed 115,767 women in the NHS, identified 508 incident PD cases and used multivariable Cox proportional hazards models to estimate the risk of PD associated with each size fraction of PM independently. Results: In models adjusted for age in months, smoking, region, population density, caffeine and ibuprofen intake, we observed no statistically significant associations between exposure to air pollution and PD risk. The relative risk (RR) comparing the top quartile to the bottom quartile of PM exposure was 0.99 (95% Confidence Intervals (CI): 0.84,1.16) for PM10 (≤10 microns in diameter), 1.08 (95% CI: 0.81, 1.45) for PM2.5 (≤2.5 microns in diameter), and 0.92 (95% CI: 0.71, 1.19) for PM10–2.5 (2.5 to 10 microns in diameter). Conclusions: In this study, we found no evidence that exposure to air pollution is a risk factor for PD.
The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson’s Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia
(Public Library of Science, 2015) Chen, Xiqun; Wales, Pauline; Quinti, Luisa; Zuo, Fuxing; Moniot, Sébastien; Herisson, Fanny; Rauf, Nazifa Abdul; Wang, Hua; Silverman, Richard B.; Ayata, Cenk; Maxwell, Michelle M.; Steegborn, Clemens; Schwarzschild, Michael; Outeiro, Tiago F.; Kazantsev, Aleksey G.
Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson’s disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson’s disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson’s disease, and previously in Huntington’s disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases.
A Prospective Analysis of Airborne Metal Exposures and Risk of Parkinson Disease in the Nurses’ Health Study Cohort
(NLM-Export, 2014) Palacios, Natalia; Fitzgerald, Kathryn C.; Roberts, Andrea L.; Hart, Jaime; Weisskopf, Marc; Schwarzschild, Michael; Ascherio, Alberto; Laden, Francine
Background: Exposure to metals has been implicated in the pathogenesis of Parkinson disease (PD). Objectives: We sought to examine in a large prospective study of female nurses whether exposure to airborne metals was associated with risk of PD. Methods: We linked the U.S. Environmental Protection Agency (EPA)’s Air Toxics tract-level data with the Nurses’ Health Study, a prospective cohort of female nurses. Over the course of 18 years of follow-up from 1990 through 2008, we identified 425 incident cases of PD. We examined the association of risk of PD with the following metals that were part of the first U.S. EPA collections in 1990, 1996, and 1999: arsenic, antimony, cadmium, chromium, lead, manganese, mercury, and nickel. To estimate hazard ratios (HRs) and 95% CIs, we used the Cox proportional hazards model, adjusting for age, smoking, and population density. Results: In adjusted models, the HR for the highest compared with the lowest quartile of each metal ranged from 0.78 (95% CI: 0.59, 1.04) for chromium to 1.33 (95% CI: 0.98, 1.79) for mercury. Conclusions: Overall, we found limited evidence for the association between adulthood ambient exposure to metals and risk of PD. The results for mercury need to be confirmed in future studies. Citation: Palacios N, Fitzgerald K, Roberts AL, Hart JE, Weisskopf MG, Schwarzschild MA, Ascherio A, Laden F. 2014. A prospective analysis of airborne metal exposures and risk of Parkinson disease in the Nurses’ Health Study Cohort. Environ Health Perspect 122:933–938; http://dx.doi.org/10.1289/ehp.1307218
Meeting Report: Consensus Statement—Parkinson’s Disease and the Environment: Collaborative on Health and the Environment and Parkinson’s Action Network (CHE PAN) Conference 26–28 June 2007.
(National Institute of Environmental Health Sciences, 2008) Bronstein, Jeff; Carvey, Paul; Chen, Honglei; Cory-Slechta, Deborah; DiMonte, Donato; Duda, John; English, Paul; Grate, Stephen; Hansen, Johnni; Hoppin, Jane; Jewell, Sarah; Kamel, Freya; Koroshetz, Walter; Langston, James W.; Logroscino, Giancarlo; Nelson, Lorene; Ravina, Bernard; Rocca, Walter; Schettler, Ted; Scott, Bill; Seegal, Richard; Singleton, Andrew; Steenland, Kyle; Tanner, Caroline M.; Van Den Eeden, Stephen; Goldman, Samuel; Ross, George W.; Schwarzschild, Michael; Weisskopf, Marc
Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk. Methods: In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD. Results: We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs. Conclusions: PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.
Air Pollution and Risk of Parkinson’s Disease in a Large Prospective Study of Men
(Environmental Health Perspectives, 2017) Palacios, Natalia; Fitzgerald, Kathryn C.; Hart, Jaime; Weisskopf, Marc; Schwarzschild, Michael; Ascherio, Alberto; Laden, Francine
Background: Exposure to air pollution has been implicated in a number of adverse health outcomes, and the effect of particulate matter (PM) on the brain is beginning to be recognized. Objectives: We aimed to examine whether exposure to PM air pollution is related to risk of Parkinson's disease (PD) in the Health Professionals Follow-up Study (HPFS), a large prospective cohort of U.S. men. Methods: We prospectively followed 50,352 men in the HPFS, a large prospective cohort of U.S. men, and identified 550 incident PD cases. Cumulative average exposure to various size fractions of PM [PM10 (≤10μm microns in diameter), PM2.5 (≤2.5μm in diameter), and PM2.5–10 (between 2.5 and 10μm in diameter)] up to 2 years before the onset of PD was estimated using a spatiotemporal model by linking each participant’s place of residence throughout the study with location-specific PM levels. We used multivariable Cox proportional hazards models to independently estimate the risk of PD associated with each size fraction of PM. Results: In models adjusted for age, smoking, region, and population density, we did not observe statistically significant associations between exposure to PM and PD risk. In analyses considering cumulative average PM exposure, the comparing the top to the bottom quintile of PM exposure was 0.85 [95% confidence interval (CI): (0.63, 1.15)] for PM10, 0.97 [95% CI: (0.72, 1.32)] for PM2.5, and 0.88 [95% CI: (0.64, 1.22)] for hazard ratio (HR) PM2.5–10. The results did not change markedly when restricted to men who did not move during the study or when stratified by smoking status or population density. Conclusions: In this study, we found no evidence that exposure to air pollution is a risk factor for PD in men. https://doi.org/10.1289/EHP259