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A multi-institutional team based at Massachusetts General Hospital (MGH) has discovered how a potential treatment strategy for Huntington disease (HD) produces its effects, verified its action in human cells and identified a previously unknown deficit in neural stem cells from patients with HD. In their report published in Proceedings of the National Academy of Sciences, the team describes finding how a group of compounds activates the NRF2 molecular pathway, which protects cells from several damaging influences, and also discovering that NRF2-mediated activity appears to be impaired in neural stem cells from the brains of HD patients. "NRF2 activates the expression of a large number of detoxification, antioxidant and anti-inflammatory genes, as well as genes involved in the clearance of damaged proteins," says Aleksey Kazantsev, PhD, who led the study as an investigator at the MassGeneral Institute for Neurodegenerative Disease (MIND). "Previous work in cellular and animal models of HD demonstrated the neuroprotective efficacy of NRF2, but data in human HD cells have been lacking, precluding evaluation of the therapeutic potential of NRF2 signaling." A 2016 study led by Kazantsev identified a compound, which the investigators named MIND4, that appeared to protect against HD-associated neurodegeneration in two ways - by activating the NRF2-mediated pathway and by inhibiting the regulatory enzyme SIRT2, a strategy also being investigated to treat Parkinson's disease. A related compound, called MIND4-17, was found to only activate the NRF2 pathway but to do so more powerfully than did MIND4. The current investigation's overall goal was to examine whether the NRF2 activation responses observed in that study were also present in human cells, indicating their potential for therapeutic development. An initial series of experiments in cellular and animal models replicated the previous finding of powerful activation of the NRF2 pathway by MIND4-17 and also showed increased expression of antioxidant proteins further down the pathway. The investigators then found that MIND4-17 acts by mimicking the same process that activates the NRF2 pathway in response to oxidative stress. In stress-free conditions NRF2 is bound into a complex by two other proteins, one of which mediates a process leading to the breakdown of NRF2. MIND4-17 binds to and modifies the mediating protein in way that changes the shape and arrests formation of the protein complex, thereby allowing newly synthesized NRF2 to escape degradation and move to the nucleus where it can activate protective antioxidant genes. NRF2 activation also induced anti-inflammatory effects in microglia and macrophages, immune cells known to infiltrate the brain in late-stage HD; and treatment with MIND4, which crosses the blood-brain barrier, reduced levels of a key inflammatory protein in a mouse model of HD. MIND4-17 treatment of monocytes - the precursors to macrophages - from patients with HD reduced their production of inflammatory cytokines. In human neural stem cells from patients with HD - cells reflecting a range of the CAG nucleotide repeats found in the mutated gene that underlies the disorder - NRF2 activation in response to MIND4-17 was found to be reduced at levels correlating with the number of repeats. While the response in cells with the number of CAG repeats typical for adult onset of HD symptoms was about half what was seen in control cells, in cells with the extreme number of repeats associated with juvenile-onset HD, MIND4-17 produced no detectable NRF2 activation. In a cell line in which extreme CAG repeats had been reduced to a nonpathologic level, MIND4-17 induced NRF2 activation at levels similar to those of control cells. "These results in neural stem cells from HD patients are probably the most intriguing and significant of the study," says Kazantsev, who is now based at the Cambridge, Mass., startup company Effective Therapeutics, LLC, but continues collaborating with colleagues at MGH and other institutions. "It is interesting that antioxidant responses to NRF2 activation were only reduced in neural stem cells, which are known to be depleted in patients with HD, but remained intact in non-neuronal cells. While these results strongly suggest NRF2 activation as a promising therapeutic avenue, that can only be confirmed by human clinical trials." Since MIND4-17 is unable to penetrate the blood brain barrier, future work is needed to develop powerful NRF2-activating compounds with enhanced brain permeability and to test their efficacy in models of HD and other neurodegenerative disorders. The previous and current work regarding therapeutic use of MIND4 and related compounds for conditions including HD, Parkinson disease and amytrophic lateral sclerosis is covered by an MGH-filed patent application. This work is a collaborative effort of 39 co-authors at 13 academic laboratories and two companies, with significant contributions from Luisa Quinti, PhD, Xiqun Chen, MD, and Kimberly Kegel-Gleason, PhD, MassGeneral Institute for Neurodegenerative Disease; Sharadha Dayalan Naidu, PhD, and Albena Dinkova-Kostova, PhD, University of Dundee, Scotland; and Ulrike Träger PhD and Sarah Tabrizi, MBChB, PhD, University College London. Support for the study includes National Institutes of Health grants U01-NS066912, R01-NS04528 and GM080356; Biotechnology and Biological Sciences Research Council grants BB/J007498/1 and BB/L01923X/1; and Cancer Research UK grant C20953/A18644. 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, genomic medicine, 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."


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.


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.


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.


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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