Modulation of Nuclear Transport and the Nuclear Pore Complex in Sporadic ALS
Abstract
Novel therapies are urgently needed for amyotrophic lateral sclerosis (ALS), a fatal degenerative disease affecting motor neurons in the brain and spinal cord. Although significant progress has been made with genetic treatments for patients with inherited disease, 90% of patients with sporadic ALS do not have a family history. Because the cause is still unknown, sporadic ALS has been difficult to model and test in the laboratory setting. However, with the recent development of induced pluripotent stem cells (iPS cells), blood or skin cells from sporadic ALS patients can be reprogrammed into stem cells and differentiated into neurons in order to study disease biology and test candidate drugs. Here, we will use the iPS model to evaluate and test therapies targeting nuclear transport, the fundamental process by which cells shuttle proteins and RNA in and out of the nucleus. Growing data suggest that defects in nuclear transport are a common pathway for neurodegeneration, and in preliminary studies we have identified transport defects in a subset of sporadic ALS iPS lines. We will expand these studies to 35 patient and 20 control lines, to generate a comprehensive library of sporadic ALS nuclear transport defects and test response to promising nuclear transport therapies. These studies will identify lead therapeutic candidates for nuclear transport defects in sporadic ALS and also uncover specific cell biologic signatures that may help us predict which patients will respond to specific therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910209
Entities
People
- Jeffrey D Rothstein
Organizations
- Johns Hopkins University
- United States Army