Modulation of Nuclear Transport and the Nuclear Pore Complex in Sporadic ALS
Abstract
Growing evidence points to disruption of nuclear transport in neurodegenerative diseases, (recently reviewed). Recently, our laboratory and others identified defects in nucleocytoplasmic transport in models of familial ALS due to a hexanucleotide repeat expansion in C9orf72 (C9), across multiple model systems, patient induced pluripotent stem cell (iPSC)-derived neurons, and postmortem tissue. Working with collaborators in academics and industry, we have now identified multiple candidate therapies for reversing C9-mediated nuclear transport deficits. We have also begun to screen for nuclear transport deficits in sporadic ALS (sALS) iPSC-derived motor neurons (iPSN). Although more heterogeneous than C9-ALS, we find evidence of both nuclear transport and nuclear pore complex disruption in sALS iPSN. These data suggest that sALS, like C9-ALS, involves a defect in nuclear transport that is a promising and druggable target. In the proposed aims, we will further define the nuclear transport deficits in sALS iPSN, and test candidate drugs for reversing these deficits. This study will identify lead agents for reversing nuclear transport defects in sALS and allow us to correlate specific "nuclear transport signatures" at the level of iPSN with response to therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1154983
Entities
People
- Jeffrey D Rothstein
Organizations
- Johns Hopkins University