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Systematic Comparison of the Effects of Alpha-synuclein Mutations on Its Oligomerization and Aggregation
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نویسنده
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lázaro d.f. ,rodrigues e.f. ,langohr r. ,shahpasandzadeh h. ,ribeiro t. ,guerreiro p. ,gerhardt e. ,kröhnert k. ,klucken j. ,pereira m.d. ,popova b. ,kruse n. ,mollenhauer b. ,rizzoli s.o. ,braus g.h. ,danzer k.m. ,outeiro t.f.
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منبع
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plos genetics - 2014 - دوره : 10 - شماره : 11
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چکیده
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Aggregation of alpha-synuclein (asyn) in lewy bodies and lewy neurites is the typical pathological hallmark of parkinson's disease (pd) and other synucleinopathies. furthermore,mutations in the gene encoding for asyn are associated with familial and sporadic forms of pd,suggesting this protein plays a central role in the disease. however,the precise contribution of asyn to neuronal dysfunction and death is unclear. there is intense debate about the nature of the toxic species of asyn and little is known about the molecular determinants of oligomerization and aggregation of asyn in the cell. in order to clarify the effects of different mutations on the propensity of asyn to oligomerize and aggregate,we assembled a panel of 19 asyn variants and compared their behaviour. we found that familial mutants linked to pd (a30p,e46k,h50q,g51d and a53t) exhibited identical propensities to oligomerize in living cells,but had distinct abilities to form inclusions. while the a30p mutant reduced the percentage of cells with inclusions,the e46k mutant had the opposite effect. interestingly,artificial proline mutants designed to interfere with the helical structure of the n-terminal domain,showed increased propensity to form oligomeric species rather than inclusions. moreover,lysine substitution mutants increased oligomerization and altered the pattern of aggregation. altogether,our data shed light into the molecular effects of asyn mutations in a cellular context,and established a common ground for the study of genetic and pharmacological modulators of the aggregation process,opening new perspectives for therapeutic intervention in pd and other synucleinopathies. © 2014 lázaro et al.
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آدرس
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department of neurodegeneration and restorative research,center for nanoscale microscopy and molecular physiology of the brain university medical goettingen,goettingen, Germany, department of neurodegeneration and restorative research,center for nanoscale microscopy and molecular physiology of the brain university medical goettingen,goettingen, Germany, department of neurology,ulm university,ulm, Germany, georg august university,institute for microbiology and genetics dept. of molecular microbiology and genetics,goettingen, Germany, laboratório de citotoxicidade e genotoxicidade,departamento de bioquímica - instituto de química universidade federal do rio de janeiro,rio de janeiro, Brazil, department of neurodegeneration and restorative research,center for nanoscale microscopy and molecular physiology of the brain university medical goettingen,goettingen,germany,instituto de medicina molecular,lisboa, Portugal, department of neurodegeneration and restorative research,center for nanoscale microscopy and molecular physiology of the brain university medical goettingen,goettingen, Germany, department of neuro and sensory physiology,university of göttingen medical center c/o european neuroscience institute göttingen,göttingen, Germany, department of molecular neurology,university hospital erlangen,friedrich-alexander university erlangen-nürnberg,erlangan, Germany, laboratório de citotoxicidade e genotoxicidade,departamento de bioquímica - instituto de química universidade federal do rio de janeiro,rio de janeiro, Brazil, georg august university,institute for microbiology and genetics dept. of molecular microbiology and genetics,goettingen, Germany, institute for neuropathology,university medical center goettingen,goettingen, Germany, institute for neuropathology,university medical center goettingen,goettingen,germany,the department for neurosurgery at umg and paracelsus-elena-klinik,kassel, Germany, department of neuro and sensory physiology,university of göttingen medical center c/o european neuroscience institute göttingen,göttingen, Germany, georg august university,institute for microbiology and genetics dept. of molecular microbiology and genetics,goettingen, Germany, department of neurology,ulm university,ulm, Germany, department of neurodegeneration and restorative research,center for nanoscale microscopy and molecular physiology of the brain university medical goettingen,goettingen,germany,laboratório de citotoxicidade e genotoxicidade,departamento de bioquímica - instituto de química universidade federal do rio de janeiro,rio de janeiro, Brazil
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Authors
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