Evidence map›Paper›PMID 36121476›Full record

ArticleActa neuropathologica2022

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

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 and 18 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
3.7field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

18 citing papers in PubMed, 31 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors at 5 institutions in 3 countries.

Rachel E LackieRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Aline S de MirandaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Mei Peng LimRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Vladislav NovikovRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Nimrod MadrerThe 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.
Nadun C KarunatillekeDepartment of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Benjamin S RutledgeDepartment of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Stephanie TulloCerebral Imaging Centre, Douglas Research Institute, McGill University, Montreal, Canada.
Anne BrickendenDepartment of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Matthew E R MaitlandRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
David GreenbergThe 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.
Daniel GallinoCerebral Imaging Centre, Douglas Research Institute, McGill University, Montreal, Canada.
Wen LuoEarly 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.
Anoosha AttaranRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Irina ShlaiferEarly 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.
Esther Del Cid PelliteroEarly 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.
Caroline Schild-PoulterRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Thomas M DurcanEarly 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.
Edward A FonEarly 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.
Martin DuennwaldDepartment of Anatomy & Cell Biology, The University of Western Ontario, London, Canada.
Flavio H BeraldoRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
M Mallar ChakravartyCerebral Imaging Centre, Douglas Research Institute, McGill University, Montreal, Canada.
Timothy J BusseyRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Lisa M SaksidaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Hermona SoreqThe 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.
Wing-Yiu ChoyDepartment of Biochemistry, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada. jchoy4@uwo.ca.
Vania F PradoRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada. vprado@robarts.ca.
Marco A M PradoRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada. mprado@robarts.ca.ORCID 0000-0002-3028-5778
Western University · CAMontreal Neurological Institute and Hospital · CADouglas Mental Health University Institute · CAHebrew University of Jerusalem · ILUniversidade Federal de Minas Gerais · BR

Funding

CIHR PJT 159781CIHR PJT 162431CIHR PJT-169101
6 · The paper itself

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.

Indexed as

Intrinsically Disordered Proteinsalpha-SynucleinAnimalsHeat-Shock ProteinsHSP90 Heat-Shock ProteinsHumansMiceMolecular ChaperonesPhosphoproteinsUbiquitinsalpha-SynucleinHeat-Shock ProteinsHSP90 Heat-Shock ProteinsIntrinsically Disordered ProteinsMolecular ChaperonesPhosphoproteinsSnca protein, mouseSTIP1 protein, humanStip1 protein, mouseUbiquitinsA53TChaperoneHOPHsp70Hsp90Lewy bodyNeuropathologyParkinson’sPre-formed fibrilsSTIP1Touchscreensα-Synuclein

Identifiers

PMID36121476
PMCPMC9547791
OpenAlexW4296324589

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.