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The mechanism of sirtuin 2–mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease
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نویسنده
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de oliveira r.m. ,vicente miranda h. ,francelle l. ,pinho r. ,szegö é.m. ,martinho r. ,munari f. ,lázaro d.f. ,moniot s. ,guerreiro p. ,fonseca l. ,marijanovic z. ,antas p. ,gerhardt e. ,enguita f.j. ,fauvet b. ,penque d. ,pais t.f. ,tong q. ,becker s. ,kügler s. ,lashuel h.a. ,steegborn c. ,zweckstetter m. ,outeiro t.f.
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منبع
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plos biology - 2017 - دوره : 15 - شماره : 3
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چکیده
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Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as alzheimer and parkinson disease (pd). however,the precise molecular mechanisms involved remain unclear. here,we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein,the major component of the pathognomonic protein inclusions in pd and other synucleinopathies. we found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation,its aggregation,and autophagy. strikingly,mutants blocking acetylation exacerbate α-synuclein toxicity in vivo,in the substantia nigra of rats. our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity,demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies. © 2017 de oliveira et al.
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آدرس
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cedoc,nova medical school,faculdade de ciências médicas,universidade nova de lisboa,lisboa, Portugal, cedoc,nova medical school,faculdade de ciências médicas,universidade nova de lisboa,lisboa, Portugal, department of neurodegeneration and restorative research,university medical center göttingen,göttingen, Germany, department of neurodegeneration and restorative research,university medical center göttingen,göttingen,germany,faculty of medicine,university of porto,porto, Portugal, department of neurodegeneration and restorative research,university medical center göttingen,göttingen, Germany, instituto de medicina molecular,faculdade de medicina,universidade de lisboa,lisboa, Portugal, department for nmr-based structural biology,max planck institute for biophysical chemistry,göttingen,germany,german center for neurodegenerative diseases (dzne),göttingen, Germany, department of neurodegeneration and restorative research,university medical center göttingen,göttingen, Germany, department of biochemistry,university of bayreuth,bayreuth, Germany, department of neurodegeneration and restorative research,university medical center göttingen,göttingen, Germany, department for nmr-based structural biology,max planck institute for biophysical chemistry,göttingen, Germany, instituto de medicina molecular,faculdade de medicina,universidade de lisboa,lisboa, Portugal, instituto de medicina molecular,faculdade de medicina,universidade de lisboa,lisboa, Portugal, department of neurodegeneration and restorative research,university medical center göttingen,göttingen, Germany, instituto de medicina molecular,faculdade de medicina,universidade de lisboa,lisboa, Portugal, laboratory of molecular and chemical biology of neurodegeneration,swiss federal institute of technology lausanne (epfl),lausanne, Switzerland, laboratório de proteómica,departamento de genética humana,instituto nacional de saúde dr. ricardo jorge,lisboa, Portugal, instituto de medicina molecular,faculdade de medicina,universidade de lisboa,lisboa, Portugal, usda/ars children's nutrition research center,department of pediatrics,baylor college of medicine,houston,tx, United States, department for nmr-based structural biology,max planck institute for biophysical chemistry,göttingen, Germany, department of neurology,university medical center göttingen,university of göttingen,göttingen, Germany, laboratory of molecular and chemical biology of neurodegeneration,swiss federal institute of technology lausanne (epfl),lausanne, Switzerland, department of biochemistry,university of bayreuth,bayreuth, Germany, department for nmr-based structural biology,max planck institute for biophysical chemistry,göttingen,germany,german center for neurodegenerative diseases (dzne),göttingen,germany,department of neurology,university medical center göttingen,university of göttingen,göttingen, Germany, cedoc,nova medical school,faculdade de ciências médicas,universidade nova de lisboa,lisboa,portugal,department of neurodegeneration and restorative research,university medical center göttingen,göttingen,germany,max planck institute for experimental medicine,göttingen,germany,center for biostructural imaging of neurodegeneration,university medical center göttingen,university of göttingen,göttingen, Germany
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Authors
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