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Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo.
Lackie, Rachel E; de Miranda, Aline S; Lim, Mei Peng; Novikov, Vladislav; Madrer, Nimrod; Karunatilleke, Nadun C; Rutledge, Benjamin S; Tullo, Stephanie; Brickenden, Anne; Maitland, Matthew E R; Greenberg, David; Gallino, Daniel; Luo, Wen; Attaran, Anoosha; Shlaifer, Irina; Del Cid Pellitero, Esther; Schild-Poulter, Caroline; Durcan, Thomas M; Fon, Edward A; Duennwald, Martin; Beraldo, Flavio H; Chakravarty, M Mallar; Bussey, Timothy J; Saksida, Lisa M; Soreq, Hermona; Choy, Wing-Yiu; Prado, Vania F; Prado, Marco A M.
Afiliação
  • Lackie RE; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • de Miranda AS; Program in Neuroscience, The University of Western Ontario, London, Canada.
  • Lim MP; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Novikov V; Laboratory of Neurobiology, Department of Morphology, Institute of Biological Science, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
  • Madrer N; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Karunatilleke NC; Program in Neuroscience, The University of Western Ontario, London, Canada.
  • Rutledge BS; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Tullo S; Program in Neuroscience, The University of Western Ontario, London, Canada.
  • Brickenden A; 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.
  • Maitland MER; Department of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Greenberg D; Department of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Gallino D; Cerebral Imaging Centre, Douglas Research Institute, McGill University, Montreal, Canada.
  • Luo W; Department of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Attaran A; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Shlaifer I; Department of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Del Cid Pellitero E; 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.
  • Schild-Poulter C; Cerebral Imaging Centre, Douglas Research Institute, McGill University, Montreal, Canada.
  • Durcan TM; 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.
  • Fon EA; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Duennwald M; 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.
  • Beraldo FH; 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.
  • Chakravarty MM; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Bussey TJ; Department of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Saksida LM; 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.
  • Soreq H; 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.
  • Choy WY; Department of Anatomy & Cell Biology, The University of Western Ontario, London, Canada.
  • Prado VF; Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
  • Prado MAM; Cerebral Imaging Centre, Douglas Research Institute, McGill University, Montreal, Canada.
Acta Neuropathol ; 144(5): 881-910, 2022 11.
Article em En | MEDLINE | ID: mdl-36121476
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Alfa-Sinucleína / Proteínas Intrinsicamente Desordenadas / Proteínas de Choque Térmico Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Acta Neuropathol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Alfa-Sinucleína / Proteínas Intrinsicamente Desordenadas / Proteínas de Choque Térmico Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Acta Neuropathol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá