RESUMO
Alpha-synuclein is a major constituent of pathological intracellular inclusion bodies, a common feature of several neurodegenerative diseases. Two missense mutations in the alpha-synuclein gene have been identified in confirmed autosomal-dominant familial Parkinson's disease, which segregate with the illness. However, the physiological function of alpha-synuclein remains unknown. After biochemical investigations we have revealed tubulin to be an alpha-synuclein associated/binding protein. Here, we show that alpha-synuclein induces polymerization of purified tubulin into microtubules. Mutant forms of alpha-synuclein lose this potential. The binding site of alpha-synuclein to tubulin is identified, and co-localization of alpha-synuclein with microtubules is shown in cultured cells. To our knowledge, this is the first demonstration of microtubule-polymerizing activity of alpha-synuclein. Now we can see a striking resemblance between alpha-synuclein and tau: both have the same physiological function and pathological features, making abnormal structures in diseased brains known as synucleinopathies and tauopathies. The discovery of a physiological role for alpha-synuclein may provide a new dimension in researches into the mechanisms of alpha-synuclein-associated neurodegenerative diseases.
Assuntos
Proteínas Associadas aos Microtúbulos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Oxirredutases do Álcool , Animais , Sítios de Ligação , Encéfalo/metabolismo , Encéfalo/patologia , Células COS/metabolismo , Primers do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Espaço Intracelular/metabolismo , Espaço Intracelular/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação de Sentido Incorreto/genética , Proteínas do Tecido Nervoso/genética , Fosfoproteínas/metabolismo , Mutação Puntual/genética , Reação em Cadeia da Polimerase , Suínos , Sinucleínas , Transfecção/métodos , alfa-Sinucleína , Proteínas tau/metabolismoRESUMO
Increasing evidence suggests that alpha-synuclein is a common pathogenic molecule in several neurodegenerative diseases, particularly in Parkinson's disease. To understand alpha-synuclein pathology, we investigated molecules that interact with alpha-synuclein in human and rat brains and identified tubulin as an alpha-synuclein binding/associated protein. Tubulin co-localized with alpha-synuclein in Lewy bodies and other alpha-synuclein-positive pathological structures. Tubulin initiated and promoted alpha-synuclein fibril formation under physiological conditions in vitro. These findings suggest that an interaction between tubulin and alpha-synuclein might accelerate alpha-synuclein aggregation in diseased brains, leading to the formation of Lewy bodies.