SUMO-1 Modification on K166 of PolyQ-Expanded aTaxin-3 Strengthens Its Stability and Increases Its Cytotoxicity

Abstract

Post-translational modification by SUMO was proposed to modulate the pathogenesis of several neurodegenerative diseases. Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disease caused by polyQ-expanded ataxin-3. We have previously shown that ataxin-3 was a new target of SUMOylation in vitro and in vivo. Here we identified that the major SUMO-1 binding site was located on lysine 166. SUMOylation did not influence the subcellular localization, ubiquitination or aggregates formation of mutant-type ataxin-3, but partially increased its stability and the cell apoptosis. Our findings revealed the role of ataxin-3 SUMOylation in SCA3/MJD pathogenesis.

SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97

“…SUMOylation site identified in Atx3 expressed in HEK293 cells[45],425 is not the main SUMOylation site neither in vitro nor in COS-7 cells, 426 since the K166R mutation, contrary to what was observed in the 427 K356R mutant, did not impair SUMOylation using our assay(Fig. 2B…”

miR‐25 alleviates polyQ‐mediated cytotoxicity by silencing ATXN3

“…For the MTT assay [4], SCA3/MJD model cells established using the HEK 293T cell line (pcSCA3/MJDtr‐68Q or pcSCA3/MJDtr‐68Q‐UTR) were cultured in 96‐well plates and transfected with miRNA mimics or siATXN3‐MUT. Cells were harvested at 0, 24, and 48 h after transfection.…”

Extranuclear SUMOylation in Neurons

“…For example, α-synuclein accumulates into Lewy Bodies in PD and associated disorders, and SUMOylation of α-synuclein is strongly implicated in regulating α-synuclein solubility, although whether it promotes or reduces aggregation remains controversial [74,85,86]. Furthermore, PolyQ expansions in disease-associated proteins lead to the formation of aggregates in Huntington's Disease [87][88][89], spinobulbar muscular atrophy [90], dentatorubral-pallidoluysian atrophy [91] and a number of spinocerebellar ataxias [92][93][94], and several of the affected proteins have been reported to be modified by SUMO, resulting in altered solubility of the target protein.…”