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

Area of Science:

• Neuroscience
• Molecular Biology
• Drug Discovery

Background:

• TDP-43 pathology, characterized by aggregation and nuclear depletion, is central to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Importin-β1 (KPNB1) functions in nuclear cytoplasmic transport and as a chaperone, with increased expression shown to mitigate TDP-43 aggregation.
• Understanding KPNB1's chaperone activity is crucial for developing therapeutic strategies against TDP-43 proteinopathies.

Purpose of the Study:

• To identify and characterize a small molecule that enhances KPNB1's chaperone activity to address TDP-43 pathology.
• To investigate the therapeutic potential of this molecule in preclinical models of ALS and FTD.

Main Methods:

• Identification of JRMS, a small molecule designed to increase KPNB1's cytoplasmic availability and chaperone function.
• Assessment of JRMS effects on TDP-43 aggregation and localization in various experimental systems (cell lines, primary neurons, iPSC-derived neurons, brain slices, in vivo models).
• Evaluation of KPNB1 dependency, cytotoxicity, and impact on nuclear cytoplasmic transport (NCT) following JRMS treatment.

Main Results:

• JRMS treatment significantly reduced cytoplasmic TDP-43 aggregation and promoted its nuclear localization across diverse models.
• The therapeutic effects of JRMS were dependent on KPNB1.
• JRMS treatment did not induce cytotoxicity or disrupt basal nuclear cytoplasmic transport.

Conclusions:

• JRMS effectively enhances KPNB1 chaperone activity, offering a novel therapeutic avenue for TDP-43 proteinopathies.
• JRMS demonstrates significant potential as a treatment strategy for ALS and FTD by targeting the core TDP-43 pathology.
• Further research into JRMS could lead to effective interventions for neurodegenerative diseases characterized by TDP-43 dysfunction.