Non-SUMOylated alternative spliced isoforms of alpha-synuclein are more aggregation-prone and toxic

Modulation of α-synuclein in vitro aggregation kinetics by its alternative splice isoforms

“…This finding may be due to increased sequestration of fibrils in clumps, which are therefore less available for interaction with cells. In contrast, a recent study has demonstrated that intracellular overexpression of αSyn-112 and αSyn-98 led to greater cytotoxicity than αSyn-140 and αSyn-126, underlining a pathogenic potential of these isoforms ( 49 ). In our system, fibrils from co-aggregation and cross-seeding experiments had similar effects on cell viability as fibrils from pure αSyn-140 aggregation.…”

“…These findings can be rationalized by the high negative charge of the C-terminal region of αSyn-140, which is protective against aggregation. Previous studies on C-terminally truncated αSyn variants also reported an increased aggregation propensity compared to αSyn-140 ( 42 – 47 ), while reports using end-point aggregation assays in cultured cells have either indicated an increased or decreased aggregation propensity for αSyn-112 and αSyn-98 ( 35 , 48 , 49 ).…”

The effects of post-translational modifications on alpha-synuclein aggregation and immune cell activation in Parkinson’s disease

“…SUMOylation occurs mainly on Lys96 and Lys102 in wildtype α-syn [23] but can affect many other Lys residues of α-syn as well in diseased conditions. While SUMOylation has been reported to promote the formation of α-syn aggregates through prevention of ubiquitin linkage by competing for Lys residues and by increasing α-syn hydrophobicity [35,36], SUMOylation has also been shown to reduce aggregation in some circumstances, with Lys96 and Lys102 SUMOylation increasing α-syn solubility to limit protein fibrillation [37,38]. A summary of the amino acids in the α-syn protein which commonly undergo the PTMs discussed above is provided as Figure 1.…”