Assembly of lysine 63-linked ubiquitin conjugates by phosphorylated alpha-synuclein implies Lewy body biogenesis.
alpha-Synuclein (alpha-syn) and ubiquitin (Ub) are major protein components deposited in Lewy bodies (LBs) and Lewy neurites, which are pathologic hallmarks of idiopathic Parkinson disease (PD). Almost 90% of alpha-syn in LBs is phosphorylated at serine 129 (Ser(129)). However, the role of Ser(129)-phosphorylated alpha-syn in the biogenesis of LBs remains unclear. Here, we show that compared with coexpression of wild type (WT)alpha-syn and Ub, coexpression of phospho-mimic mutant alpha-syn (S129D) and Ub in neuro2a cells results in an increase of Ub-conjugates and the formation of ubiquitinated inclusions. Furthermore, S129D alpha-syn fails to increase the Ub-conjugates and form ubiquitinated inclusions in the presence of a K63R mutant Ub. In addition, as compared with WT alpha-syn, S129D alpha-syn increased cytoplasmic and neuritic aggregates of itself in neuro2a cells treated with H(2)O(2) and serum deprivation. These results suggest that the contribution of Ser(129)-phosphorylated alpha-syn to the Lys(63)-linked Ub-conjugates and aggregation of itself may be involved in the biogenesis of LBs in Parkinson disease and other related synucleinopathies.
Liu
Chao
C
Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology, School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, China.
Fei
Erkang
E
Jia
Nali
N
Wang
Hongfeng
H
Tao
Ruisong
R
Iwata
Atsushi
A
Nukina
Nobuyuki
N
Zhou
Jiangning
J
Wang
Guanghui
G
D000818:Animals; D015151:Immunoblotting; D002479:Inclusion Bodies; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D025801:Ubiquitin; D051844:alpha-Synuclein; D008239:Lysine