The role of ubiquitin linkages on alpha-synuclein induced-toxicity in a Drosophila model of Parkinson's disease.
Parkinson's disease (PD) is a common movement disorder marked by the loss of dopaminergic (DA) neurons in the brain stem and the presence of intraneuronal inclusions designated as Lewy bodies (LB). The cause of neurodegeneration in PD is not clear, but it has been suggested that protein misfolding and aggregation contribute significantly to the development of the disease. Misfolded and aggregated proteins are cleared by ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Recent studies suggested that different types of ubiquitin linkages can modulate these two pathways in the process of protein degradation. In this study, we found that co-expression of ubiquitin can rescue neurons from alpha-syn-induced neurotoxicity in a Drosophila model of PD. This neuroprotection is dependent on the formation of lysine 48 polyubiquitin linkage which is known to target protein degradation via the proteasome. Consistent with our results that we observed in vivo, we found that ubiquitin co-expression in the cell can facilitate cellular protein degradation by the proteasome in a lysine 48 polyubiquitin-dependent manner. Taken together, these results suggest that facilitation of proteasomal protein degradation can be a potential therapeutic approach for PD.
Lee
Francesca K M
FK
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
Wong
Azaria K Y
AK
Lee
Yuk Wa
YW
Wan
Oi Wan
OW
Chan
H Y Edwin
HY
Chung
Kenny K K
KK
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D017510:Protein Folding / Q000187:drug effects; D013378:Substantia Nigra / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000633:toxicity
D011108:Polymers; D025801:Ubiquitin; D051844:alpha-Synuclein; D046988:Proteasome Endopeptidase Complex; D008239:Lysine