The ubiquitin ligase E6-AP promotes degradation of alpha-synuclein.
Parkinson's disease (PD) is a common neurodegenerative disorder caused mainly because of the loss of dopaminergic neurons in the substantia nigra. Protein inclusions called Lewy bodies are the most common pathological hallmark of PD and other synucleinopathies. Because the main component of these inclusions is alpha-synuclein, aggregation of this protein is thought to be a key pathogenic event in this disease. In the present investigation we report that E6 associated protein (E6-AP), a HECT (homologous to E6-AP C-terminus) domain ubiquitin ligase is a component of Lewy bodies in post-mortem PD brain. In the cell culture model, we demonstrate that endogenous E6-AP colocalizes with alpha-synuclein in juxtanuclear aggregates. E6-AP is also recruited to the centrosome upon inhibition of the proteasome function suggesting its involvement in the degradation of misfolded proteins. Over-expression of E6-AP enhances the degradation of wild type as well as the mutant forms of alpha-synuclein in a proteasome-dependent manner. E6-AP also promotes the degradation of the more toxic oligomeric forms of alpha-synuclein. Our data suggests that E6-AP is involved in the clearance of alpha-synuclein.
Mulherkar
Shalaka A
SA
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon, India.
Sharma
Jaiprakash
J
Jana
Nihar Ranjan
NR
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D010300:Parkinson Disease / Q000473:pathology; D014162:Transfection / Q000379:methods; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051844:alpha-Synuclein / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D025801:Ubiquitin; D051844:alpha-Synuclein; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases