Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology

Topic: Brain proteins, microglia and lab models

Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.

Key findings

• Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization.
• These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.

Why it matters

The small molecule JRMS reduced TDP-43 aggregation and promoted its nuclear localization in cell lines, neurons, brain slices, and an in vivo model. These findings identify JRMS as a promising therapeutic strategy, but it has not yet been tested in humans.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.neurot.2026.e00834
• PubMed: 41549027
• Original source →
• Free full text: Neurotherapeutics →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{shenouda2026-41549027,
  author  = {Shenouda, Marc and Shenouda, Sandra and Kartono, Bryan and Eid, Shehab and Cheng, Cheryl and Robertson, Janice},
  title   = {{Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology}},
  journal = {Neurotherapeutics},
  year    = {2026},
  doi     = {10.1016/j.neurot.2026.e00834},
  pmid    = {41549027},
  url     = {https://doi.org/10.1016/j.neurot.2026.e00834}
}

Studies this one cites

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• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia
• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD Nature neuroscience · 2018-01-08 · usefulness score 61/100 · Lewy body dementia
• The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity Nature medicine · 2016-06-27 · usefulness score 58/100 · Lewy body dementia
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia
• The C9orf72 repeat expansion disrupts nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 57/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs Nature neuroscience · 2012-09-30 · usefulness score 56/100 · Lewy body dementia
• Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization Cell · 2015-09-01 · usefulness score 56/100 · Lewy body dementia
• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100 · Lewy body dementia
• TDP-43 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · usefulness score 56/100 · Lewy body dementia

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• TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015-04-01 · usefulness score 50/100
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