| First Author | Lackie RE | Year | 2022 |
| Journal | Acta Neuropathol | Volume | 144 |
| Issue | 5 | Pages | 881-910 |
| PubMed ID | 36121476 | Mgi Jnum | J:354599 |
| Mgi Id | MGI:7658003 | Doi | 10.1007/s00401-022-02491-8 |
| Citation | Lackie RE, et al. (2022) Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of alpha-synuclein in vivo. Acta Neuropathol 144(5):881-910 |
| abstractText | The predominantly pre-synaptic intrinsically disordered protein alpha-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 alpha-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of alpha-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated alpha-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and alpha-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of alpha-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of alpha-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ss presented elevated alpha-synuclein S129 phosphorylation accompanied by inclusions when injected with alpha-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 alpha-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in alpha-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic alpha-synuclein conformers, while alpha-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90. |
