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News Article | March 2, 2017
Site: www.chromatographytechniques.com

A gene variant that produces red hair and fair skin in humans and in mice, which increases the risk of the dangerous skin cancer melanoma, may also contribute to the known association between melanoma and Parkinson's disease. In their paper appearing in the March issue of Annals of Neurology and previously published online, Massachusetts General Hospital (MGH) investigators report that mice carrying the red hair variant of the melanocortin 1 receptor (MC1R) gene have reduced production of the neurotransmitter dopamine in the substantia nigra -- the brain structure in which dopamine-producing neurons are destroyed in Parkinson's disease (PD) -- and are more susceptible to toxins known to damage those neurons. "This study is the first to show direct influences of the melanoma-linked MC1R gene on dopaminergic neurons in the brain and may provide evidence for targeting MC1R as a novel therapeutic strategy for PD," says Xiqun Chen, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), lead and corresponding author of the report. "It also forms a foundation for further interdisciplinary investigations into the dual role of this gene in tumorigenesis within melanocytes - the pigment cells in which melanoma develops - and the degeneration of dopaminergic neurons, improving our understanding of why and how melanoma and Parkinson's disease are linked." Inherited variants of the MC1R gene determine skin pigmentation, with the most common form leading to greater production of the darker pigment called eumelanin and the red-hair-associated variant, which inactivates the gene's function, increasing production of the lighter pigment called pheomelanin. Not only does pheomelanin provide less protection from ultraviolet damage to the skin than does eumelanin, but a 2012 study led by David Fisher, chief of the MGH Department of Dermatology, director of the Cutaneous Biology Research Center and a co-author of the current study -- found it also may directly contribute to melanoma development. While patients with Parkinson's disease have a reduced risk of developing most types of cancer, their higher-than-expected risk of melanoma is well recognized, as is the increased risk of PD in patients with melanoma. Several recent studies also have found evidence suggesting increased PD risk in individuals with red-hair-associated variants of MC1R, so the current study was designed to explore that potential role of the gene in PD and specifically in dopamine-producing neurons of the substantia nigra. The team's experiments showed that, in mice with the common form of MC1R, the gene is expressed in dopamine-producing neurons in the substantia nigra. The red-haired mice in which the gene is inactivated because of a mutation were found to have fewer dopamine-producing neurons and as they aged developed a progressive decline in movement and a drop in dopamine levels. They also were more sensitive to toxic substances known to damage dopamine-producing neurons and had indications of increased oxidative stress - which the 2012 study implied was involved in pheomelanin-associated melanoma risk - in brain structures adjacent to the substantia nigra. Treatment with a substance that increases MC1R signaling reduced the susceptibility of mice with the common variant to a neurotoxin, further supporting a protective role for the gene's activity. "Since MC1R regulates pigmentation and red hair is a shared risk factor for both melanoma and Parkinson's disease, it is possible that, in both conditions, MC1R's role involves pigmentation and related oxidative stress," says Chen, an assistant professor of Neurology at Harvard Medical School. "Our findings suggest further investigation into the potential of MC1R-activating agents as novel neuroprotective therapies for PD, and together with epidemiological evidence, may offer information that could guide those carrying MC1R variants to seek advice from dermatologists or neurologists about their personal risk for melanoma and Parkinson's disease." Chen's team is continuing to pursue this line of research.


A gene variant that produces red hair and fair skin in humans and in mice, which increases the risk of the dangerous skin cancer melanoma, may also contribute to the known association between melanoma and Parkinson's disease. In their paper appearing in the March issue of Annals of Neurology and previously published online, Massachusetts General Hospital (MGH) investigators report that mice carrying the red hair variant of the melanocortin 1 receptor (MC1R) gene have reduced production of the neurotransmitter dopamine in the substantia nigra -- the brain structure in which dopamine-producing neurons are destroyed in Parkinson's disease (PD) -- and are more susceptible to toxins known to damage those neurons. "This study is the first to show direct influences of the melanoma-linked MC1R gene on dopaminergic neurons in the brain and may provide evidence for targeting MC1R as a novel therapeutic strategy for PD," says Xiqun Chen, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), lead and corresponding author of the report. "It also forms a foundation for further interdisciplinary investigations into the dual role of this gene in tumorigenesis within melanocytes - the pigment cells in which melanoma develops - and the degeneration of dopaminergic neurons, improving our understanding of why and how melanoma and Parkinson's disease are linked." Inherited variants of the MC1R gene determine skin pigmentation, with the most common form leading to greater production of the darker pigment called eumelanin and the red-hair-associated variant, which inactivates the gene's function, increasing production of the lighter pigment called pheomelanin. Not only does pheomelanin provide less protection from ultraviolet damage to the skin than does eumelanin, but a 2012 study led by David Fisher, MD, PhD - chief of the MGH Department of Dermatology, director of the Cutaneous Biology Research Center and a co-author of the current study -- found it also may directly contribute to melanoma development. While patients with Parkinson's disease have a reduced risk of developing most types of cancer, their higher-than-expected risk of melanoma is well recognized, as is the increased risk of PD in patients with melanoma. Several recent studies also have found evidence suggesting increased PD risk in individuals with red-hair-associated variants of MC1R, so the current study was designed to explore that potential role of the gene in PD and specifically in dopamine-producing neurons of the substantia nigra. The team's experiments showed that, in mice with the common form of MC1R, the gene is expressed in dopamine-producing neurons in the substantia nigra. The red-haired mice in which the gene is inactivated because of a mutation were found to have fewer dopamine-producing neurons and as they aged developed a progressive decline in movement and a drop in dopamine levels. They also were more sensitive to toxic substances known to damage dopamine-producing neurons and had indications of increased oxidative stress - which the 2012 study implied was involved in pheomelanin-associated melanoma risk - in brain structures adjacent to the substantia nigra. Treatment with a substance that increases MC1R signaling reduced the susceptibility of mice with the common variant to a neurotoxin, further supporting a protective role for the gene's activity. "Since MC1R regulates pigmentation and red hair is a shared risk factor for both melanoma and Parkinson's disease, it is possible that, in both conditions, MC1R's role involves pigmentation and related oxidative stress," says Chen, an assistant professor of Neurology at Harvard Medical School. "Our findings suggest further investigation into the potential of MC1R-activating agents as novel neuroprotective therapies for PD, and together with epidemiological evidence, may offer information that could guide those carrying MC1R variants to seek advice from dermatologists or neurologists about their personal risk for melanoma and Parkinson's disease." Chen's team is continuing to pursue this line of research. The senior author of the Annals of Neurology report is Michael Schwarzschild, MD, PhD, director of Molecular Neurobiology Laboratory at MGH-MIND. Along with David Fisher, the study's co-authors are Waijiao Cai, MD, PhD, Michael Maguire, MS, Bailiu Ya, MD, PhD, Fuxing Zuo, MD, PhD, Robert Logan, MS, Hui Li, MD, PhD, and Charles R. Vanderburg, PhD, MGH-MIND; Hongxiang Chen, MD, PhD, and Katey Robinson, PhD, MGH Cutaneous Biology Research Center; and Yang Yu, PhD, and Yinsheng Wang, PhD, University of California, Riverside. The study was supported by National Institute of Neurological Disorders and Stroke grants 1R21 NS090246-01A1 and K24 NS060991; U.S. Department of Defense grant W81XWH-11-1-0150; and grants from the National Natural Science Foundation of China, the RJG Foundation, the Michael J. Fox Foundation and the Milstein Medical Asian American Partnership Foundation. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals.


Hooli B.V.,MassGeneral Institute for Neurodegenerative Disease | Kovacs-Vajna Z.M.,University of Brescia | Mullin K.,MassGeneral Institute for Neurodegenerative Disease | Blumenthal M.A.,MassGeneral Institute for Neurodegenerative Disease | And 6 more authors.
Molecular Psychiatry | Year: 2014

Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer's disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer's disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias. © 2014 Macmillan Publishers Limited.


Walker L.C.,Emory University | Diamond M.I.,Washington University in St. Louis | Duff K.E.,Columbia University | Hyman B.T.,MassGeneral Institute for Neurodegenerative Disease
JAMA Neurology | Year: 2013

A growing body of data indicates that the propagation of pathogenic protein aggregates across neural systems, and hence the disruption of function of those neural systems, might be mediated by misfolded protein seeds that are released and taken up by anatomically connected neurons. If so, blocking this process may help arrest the progression of disease. In light of the growing spectrum of disorders involving the accumulation and spread of misfolded proteins, efforts to detect pathogenic protein aggregates and impede their movement between cells could change how we diagnose and treat neurodegenerative diseases. © 2013 American Medical Association. All rights reserved.


Sachse C.C.,MassGeneral Institute for Neurodegenerative Disease | Kim Y.H.,MassGeneral Institute for Neurodegenerative Disease | Kim Y.H.,Korea Basic Science Institute | Agsten M.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 4 more authors.
FASEB Journal | Year: 2013

BACE1 and presenilin (PS)/γ-secretase play a major role in Alzheimer's disease pathogenesis by regulating amyloid-β peptide generation. We recently showed that these secretases also regulate the processing of voltage-gated sodium channel auxiliary β-subunits and thereby modulate membrane excitability. Here, we report that KCNE1 and KCNE2, auxiliary subunits of voltage-gated potassium channels, undergo sequential cleavage mediated by either γ-secretase and PS/γ-secretase or BACE1 and PS/γ-secretase in cells. Elevated γ-secretase or BACE1 activities increased Cterminal fragment (CTF) levels of KCNE1 and 2 in human embryonic kidney (HEK293T) and rat neuroblastoma (B104) cells. KCNE-CTFs were then further processed by PS/γ-secretase to KCNE intracellular domains. These KCNE cleavages were specifically blocked by chemical inhibitors of the secretases in the same cell models. We also verified our results in mouse cardiomyocytes and cultured primary neurons. Endogenous KCNE1- and KCNE2-CTF levels increased by 2- to 4-fold on PS/γ-secretase inhibition or BACE1 overexpression in these cells. Furthermore, the elevated BACE1 activity increased KCNE1 processing and shifted KCNE1/KCNQ1 channel activation curve to more positive potentials in HEK cells. KCNE1/KCNQ1 channel is a cardiac potassium channel complex, and the positive shift would lead to a decrease in membrane repolarization during cardiac action potential. Together, these results clearly showed that KCNE1 and KCNE2 cleavages are regulated by BACE1 and PS/γ-secretase activities under physiological conditions. Our results also suggest a functional role of KCNE cleavage in regulating voltage-gated potassium channels. © FASEB.


Gomperts S.N.,MassGeneral Institute for Neurodegenerative Disease
Current Neurology and Neuroscience Reports | Year: 2014

Cognitive impairment and dementia are significant sequelae of Parkinson disease (PD) and comprise a key feature of dementia with Lewy bodies (DLB), a disease with similar clinical and neuropathological features. Multiple independent causes have been implicated in PD dementia (PDD) and DLB, among them the accumulation of β-amyloid, a neuropathological hallmark of Alzheimer disease. Over the last decade, PET imaging has emerged as a viable method to measure amyloid burden in the human brain and relate it to neurodegenerative diseases. This article reviews what amyloid imaging has taught us about PDD and DLB. Current data suggest that brain amyloid deposition tends to be more marked in DLB, yet contributes to cognitive impairment in both DLB and PD. These results are broadly consistent with neuropathology and CSF studies. β-Amyloid may interact synergistically with other pathological processes in PD and DLB to contribute to cognitive impairment. © 2014 Springer Science+Business Media.


Hung A.Y.,Massachusetts General Hospital | Schwarzschild M.A.,Massachusetts General Hospital | Schwarzschild M.A.,MassGeneral Institute for Neurodegenerative Disease
Neurotherapeutics | Year: 2014

Dopamine depletion resulting from degeneration of nigrostriatal dopaminergic neurons is the primary neurochemical basis of the motor symptoms of Parkinson's disease (PD). While dopaminergic replacement strategies are effective in ameliorating these symptoms early in the disease process, more advanced stages of PD are associated with the development of treatment-related motor complications and dopamine-resistant symptoms. Other neurotransmitter and neuromodulator systems are expressed in the basal ganglia and contribute to the extrapyramidal refinement of motor function. Furthermore, neuropathological studies suggest that they are also affected by the neurodegenerative process. These non-dopaminergic systems provide potential targets for treatment of motor fluctuations, levodopa-induced dyskinesias, and difficulty with gait and balance. This review summarizes recent advances in the clinical development of novel pharmacological approaches for treatment of PD motor symptoms. Although the non-dopaminergic pipeline has been slow to yield new drugs, further development will likely result in improved treatments for PD symptoms that are induced by or resistant to dopamine replacement. © 2013 The American Society for Experimental NeuroTherapeutics, Inc.


Lu Z.,University of Wyoming | Marks E.,University of Wyoming | Chen J.,University of Wyoming | Moline J.,University of Wyoming | And 8 more authors.
Neurobiology of Disease | Year: 2014

Disruption of redox homeostasis is a prominent feature in the pathogenesis of Huntington's disease (HD). Selenium an essential element nutrient that modulates redox pathways and has been reported to provide protection against both acute neurotoxicity (e.g. methamphetamine) and chronic neurodegeneration (e.g. tauopathy) in mice. The objective of our study was to investigate the effect of sodium selenite, an inorganic form of selenium, on behavioral, brain degeneration and biochemical outcomes in the N171-82Q Huntington's disease mouse model. HD mice, which were supplemented with sodium selenite from 6 to 14 weeks of age, demonstrated increased motor endurance, decreased loss of brain weight, decreased mutant huntingtin aggregate burden and decreased brain oxidized glutathione levels. Biochemical studies revealed that selenite treatment reverted HD-associated changes in liver selenium and plasma glutathione in N171-82Q mice and had effects on brain selenoprotein transcript expression. Further, we found decreased brain selenium content in human autopsy brain. Taken together, we demonstrate a decreased selenium phenotype in human and mouse HD and additionally show some protective effects of selenite in N171-82Q HD mice. Modification of selenium metabolism results in beneficial effects in mouse HD and thus may represent a therapeutic strategy. © 2014 Elsevier Inc.


Ciccarese P.,Harvard University | Ciccarese P.,Massachusetts General Hospital | Soiland-Reyes S.,University of Manchester | Clark T.,Harvard University | Clark T.,MassGeneral Institute for Neurodegenerative Disease
IEEE Internet Computing | Year: 2013

The W3C Open Annotation Data Model provides facilities for annotating content directly on the Web without changing the original content. Third-party semantic annotations of content are now emerging as first-class objects on the Web. © 2013 IEEE.


Schwarzschild M.A.,MassGeneral Institute for Neurodegenerative Disease
JAMA Neurology | Year: 2014

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. MAINOUTCOMESAND 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 © Copyright 2014 American Medical Association. All rights reserved.

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