Therapeutic Modulation of HSF1-Dependent Gene Expression to Alleviate Motor Neuron Dysfunction in ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating disease resulting from loss of motor neurons, leading to paralysis and eventually death. There are no effective therapies for ALS. The major disease hallmark found in the vast majority (>90%) of all ALS patients is called TDP-43, a protein that accumulates in the brain and spinal cord and is implicated in the death of neurons. Unfortunately, targeting or removing TDP-43 with drugs is not a logical step forward, as reducing overall TDP-43 levels can be quite toxic to cells, posing unique challenges in devising new therapies for the majority of sporadic ALS patients. Our recent work suggests that activation of HSF-1, a critical protein that controls the cells ability to refold toxic aggregates in the cell, is capable of preventing TDP-43 from accumulating and therefore may restore normal cellular function to diseased neurons that are affected by ALS. Therefore, we will test whether HSF-1 activator drugs represent a new avenue to explore for therapies that could prolong the survival of ALS patients. The implications of our study are very straightforward; preclinical testing of new drugs that slow disease progression by preventing TDP-43 accumulation could lead to new and effective ALS drugs. We made significant progress toward this goal already by showing that a particular drug, called HSF1A, which turns on HSF-1, is able to prevent TDP-43 from aggregating in cells grown in a dish. Now, our goal is to move this idea forward and test the extent that HSF1A produces a therapeutic response in animal models of ALS. Our study could dramatically accelerate the development of new drugs that act to disaggregate and therefore reduce toxic forms of TDP-43; these drugs could have a major impact on the field, as they represent potential therapies for the vast majority of patients currently afflicted by ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910466
Entities
People
- Todd J Cohen
Organizations
- United States Army
- University of North Carolina at Chapel Hill