Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo.

Abstract

The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated α-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and α-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90.

• Authors: Rachel E Lackie, Aline S de Miranda, Mei Peng Lim, Vladislav Novikov, Nimrod Madrer, Nadun C Karunatilleke, Benjamin S Rutledge, Stephanie Tullo, Anne Brickenden, Matthew E R Maitland, David Greenberg, Daniel Gallino, Wen Luo, Anoosha Attaran, Irina Shlaifer, Esther Del Cid Pellitero, Caroline Schild-Poulter, Thomas M Durcan, Edward A Fon, Martin Duennwald, Flavio H Beraldo, M Mallar Chakravarty, Timothy J Bussey, Lisa M Saksida, Hermona Soreq, Wing-Yiu Choy, Vania F Prado, Marco A M Prado
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 144 Issue 5 Pg. 881-910 (11 2022) ISSN: 1432-0533 [Electronic] Germany
• PMID: 36121476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• HSP90 Heat-Shock Proteins
• Heat-Shock Proteins
• Intrinsically Disordered Proteins
• Molecular Chaperones
• Phosphoproteins
• STIP1 protein, human
• Snca protein, mouse
• Stip1 protein, mouse
• Ubiquitins
• alpha-Synuclein

Topics

• Animals
• HSP90 Heat-Shock Proteins (chemistry, metabolism)
• Heat-Shock Proteins (metabolism)
• Humans
• Intrinsically Disordered Proteins
• Mice
• Molecular Chaperones (metabolism)
• Phosphoproteins
• Ubiquitins
• alpha-Synuclein (metabolism, toxicity)