title: Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation.
abstract: Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are characterized pathologically by intraneuronal inclusions called Lewy bodies (LBs) and Lewy neurites. A major component of these inclusions is the protein α-synuclein, which is natively unfolded but forms oligomers and insoluble fibrillar aggregates under pathological conditions. Although α-synuclein is known to undergo several posttranslational modifications, the contribution of SUMOylation to α-synuclein aggregation and the pathogenesis of α-synucleinopathies have not been elucidated. Here, we provide evidence that aggregates and inclusions formed as a result of impaired proteasome activity contain SUMOylated α-synuclein. Additionally, SUMO1 is present in the halo of LBs colocalizing with α-synuclein in the brains of PD and DLB patients. Interestingly, SUMOylation does not affect the ubiquitination of α-synuclein. These findings suggest that proteasomal dysfunction results in the accumulation of SUMOylated α-synuclein and subsequently its aggregation, pointing to the contribution of this posttranslational modification to the pathogenesis of inclusion formation in α-synucleinopathies.
authors.affiliation: FCB-Pharmicell, Seongnam-si, Gyeonggi-do 462-806, Republic of Korea.
authors.forename: Yong Man
authors.initials: YM
authors.lastname: Kim
authors.forename: Won Hee
authors.initials: WH
authors.lastname: Jang
authors.forename: Martha M
authors.initials: MM
authors.lastname: Quezado
authors.forename: Yohan
authors.initials: Y
authors.lastname: Oh
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
authors.forename: Eunsung
authors.initials: E
authors.lastname: Junn
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016631:Lewy Bodies / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020961:Lewy Body Disease / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D046911:Macromolecular Substances / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000502:physiology; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D046911:Macromolecular Substances; D061988:Proteasome Inhibitors; D025842:SUMO-1 Protein; D051844:alpha-Synuclein; D046988:Proteasome Endopeptidase Complex