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

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Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2022-09-19 , DOI: 10.1007/s00401-022-02491-8
Rachel E Lackie _{1,

2} , Aline S de Miranda _{1,

3} , Mei Peng Lim _{1,

2} , Vladislav Novikov _{1,

2} , Nimrod Madrer ₄ , Nadun C Karunatilleke ₅ , Benjamin S Rutledge ₅ , Stephanie Tullo ₆ , Anne Brickenden ₅ , Matthew E R Maitland _{1,

5} , David Greenberg ₄ , Daniel Gallino ₆ , Wen Luo ₇ , Anoosha Attaran ₁ , Irina Shlaifer ₇ , Esther Del Cid Pellitero ₇ , Caroline Schild-Poulter _{1,

5} , Thomas M Durcan ₇ , Edward A Fon ₇ , Martin Duennwald ₈ , Flavio H Beraldo ₁ , M Mallar Chakravarty ₆ , Timothy J Bussey _{1,

2,

9} , Lisa M Saksida _{1,

2,

9} , Hermona Soreq ₄ , Wing-Yiu Choy ₅ , Vania F Prado _{1,

2,

8,

9} , Marco A M Prado _{1,

2,

8,

9}

Affiliation

Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Program in Neuroscience, The University of Western Ontario, London, Canada.
Laboratory of Neurobiology, Department of Morphology, Institute of Biological Science, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
The Edmond and Lily Safra Center for Brain Sciences, Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Cerebral Imaging Centre, Douglas Research Institute, McGill University, Montreal, Canada.
Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
Department of Anatomy & Cell Biology, The University of Western Ontario, London, Canada.
Department of Physiology and Pharmacology, The University of Western Ontario, London, Canada.

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.

中文翻译：

应激诱导磷蛋白 1 (HOP/STI1/STIP1) 在体内调节 α-突触核蛋白的积累和毒性

突触前本质上无序的主要蛋白 α-突触核蛋白在突触核蛋白病（例如帕金森病 (PD) 和路易体痴呆 (DLB)）中容易发生错误折叠和聚集。分子伴侣在蛋白质错误折叠疾病中起着重要作用，伴侣机制的成员通常沉积在路易体中。在这里，我们显示 Hsp90 共伴侣 STI1 共免疫沉淀 α-突触核蛋白，并与 Hsp90 和 Hsp70 共同沉积在两种 α-突触核蛋白错误折叠小鼠模型的不溶性蛋白质组分中。STI1 和 Hsp90 还与泛素阳性包涵体中的丝状 S129 磷酸化 α-突触核蛋白广泛共定位。在 PD 人脑中，STI1 转录物增加，而在神经健康的大脑中，STI1 和 α-突触核蛋白转录物相关。核磁共振 (NMR) 分析揭示了 α-突触核蛋白与 STI1 的直接相互作用，并表明 STI1 TPR2A（而非 TPR1 或 TPR2B 结构域）与 α-突触核蛋白的 C 末端结构域相互作用。在体外，STI1 TPR2A 结构域通过 Polo 样激酶 3 促进 S129 磷酸化。此外，当注射 α-突触核蛋白预形成的原纤维时，过表达 STI1 和 Hsp90ß 的小鼠呈现升高的 α-突触核蛋白 S129 磷酸化并伴有内含物。相反，STI1 功能降低会减少蛋白质包涵体形成、S129 α-突触核蛋白磷酸化，同时减轻运动和认知缺陷以及 α-突触核蛋白过度表达小鼠的细观脑萎缩。我们的研究结果揭示了一个恶性循环，其中 STI1 促进了有毒 α-突触核蛋白构象异构体的产生和积累，

更新日期：2022-09-20

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