STIP1/HOP Promotes the Formation of Cytotoxic α-Synuclein Oligomers
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The accumulation of alpha-synuclein (a-Syn) as toxic polymorphic oligomers, and subsequently in Lewy bodies is a pathological hallmark of Parkinson’s disease and other synucleinopathies. The toxicity of a-Syn appears to depend at least in part on its interaction with the co-chaperone STIP1. In mouse models of synucleinopathy STIP1 has bidirectional effects on a-Syn, with overexpression of STIP1 aggravating a-Syn toxicity, whereas knockdown of this co-chaperone improves toxicity and behavioural phenotypes. Here, we unravel the mechanisms by which STIP1 and its human homologue HOP regulate the neurotoxicity of a-Syn. Specifically, the TPR2A domain of STIP1/HOP directly interacts with two binding motifs in the C-terminus of a-Syn in a dynamic manner, thereby inhibiting the formation of a-Syn fibrils while promoting the accumulation of amorphous a-Syn assemblies that contain cytotoxic oligomeric species. Our data thus suggest a previously unknown molecular mechanism by which STIP1/HOP, and possibly other interacting proteins, participate in a-Syn toxicity. Targeting this new mechanism may provide novel strategies for treating synucleinopathies.
