Evidence map›Paper›PMID 42127909›Full record

ArticleMolecular cell2026

High-throughput screening approach identifies substrate-selective Hsp104 variants that counter amyloid seeding with diminished off-target effects.

Jeremy J Ryan, Karlie R Miller, Anuradhika Puri, Macy L Sprunger, Madalyn M Bochantine, April Lopez, Sheng Chen, Aaron Bao, Cendi Ling, Andy Xu and 7 more

Abstract read
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In one paragraph

Article in Molecular cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
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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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

17 authors.

Jeremy J RyanDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Karlie R MillerDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Anuradhika PuriDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Macy L SprungerDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Madalyn M BochantineDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
April LopezDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Sheng ChenDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Aaron BaoDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Cendi LingDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Andy XuDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Braxton BellDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Brian S SohnDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Leo LiDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Cynthia ChangDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Kalid MohammedDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA.
Max V StallerDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Meredith E JackrelDepartment of Chemistry, Washington University, St. Louis, MO 63130, USA. Electronic address: mjackrel@wustl.edu.

Funding

Elucidating the roles of protein disaggregases and developing enhanced diaggregases to counter diverse protein-misfolding disordersR35GM153303 · NIGMS · WASHINGTON UNIVERSITY · PI Meredith E. Jackrel · 2024 to 2026
$1.4M
HIGH-THROUGHPUT FUNCTIONAL INTERROGATION OF MAMMALIAN ACTIVATION DOMAINSK99GM131022 · NIGMS · WASHINGTON UNIVERSITY · PI STALLER, MAX VALENTIN · 2019 to 2020
$200k
NIGMS NIH HHS K99 GM131022NIGMS NIH HHS R35 GM153303
6 · The paper itself

Abstract

Hsp104, a yeast protein-remodeling factor, can disaggregate misfolded proteins implicated in neurodegeneration. Although many potentiated Hsp104 variants have been generated, suboptimal properties have limited their application in mammalian systems. Here, we present the development of a high-throughput screening approach for identifying enhanced Hsp104 variants. To screen a large library of variants in parallel and with a quantitative output, we coupled a live-or-die yeast-based selection with next-generation sequencing. The identified Hsp104 variants solubilize preformed α-synuclein and TDP-43 aggregates, inhibit seeding of preformed α-synuclein fibrils in mammalian biosensor cells, restore TDP-43 splicing of native targets, and have diminished off-target toxicity in mammalian cells. Certain variants show distinct changes in ATP hydrolysis, which we suggest is the key driver of these improved properties. We anticipate that our approach is broadly applicable to a range of protein engineering targets to allow coupling of a phenotypic readout to high-throughput quantitative analysis of variants in parallel.

Indexed as

alpha-SynucleinAmyloidDNA-Binding ProteinsHeat-Shock ProteinsHigh-Throughput Screening AssaysSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsAdenosine TriphosphateAnimalsHEK293 CellsHumansMutationProtein AggregatesProtein EngineeringSubstrate SpecificityAdenosine Triphosphatealpha-SynucleinAmyloidDNA-Binding ProteinsHeat-Shock ProteinsHsP104 protein, S cerevisiaeProtein AggregatesSaccharomyces cerevisiae Proteinsaggregateamyloidchaperonedeep-mutational scanningdisaggregaseHsp104protein engineering∝-synucleinTDP-43

Identifiers

PMID42127909
PMCPMC13238597

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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.