Enhancing Proteostasis to Combat Age-Related Neurodegenerative Disorders

2009 new Scholar Award in aging

As life spans increase through improvements in medicine and public health, the prevalence of devastating nerve degeneration diseases will inexorably increase to become one of the most severe obstacles to living longer, more fulfilling lives. We are in urgent need of new concepts and approaches to combat several lethal nerve degeneration disorders including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), which threaten to devastate our aging population. These disorders are associated with the clumping of specific proteins into inactive and toxic assemblies. Surprisingly, humans appear to have no mechanism to reverse this clumping and to restore proteins to function. However, hope may spring from an unlikely source, the bakerís yeast. Yeast express a protein called Hsp104, which is able to dissolve and reactivate proteins that are trapped in toxic and defective assemblies. Hence, we aim to eliminate toxic protein accumulations using Hsp104. We also aim to engineer Hsp104 to work more effectively in this process. We are focusing on two specific proteins that form toxic assemblies: tau, which forms toxic assemblies in Alzheimer's disease, and TDP-43, which forms toxic assemblies in ALS. These studies will provide the foundations for new approaches to attack several devastating disorders that plague humankind.
James Shorter PhD
University of Pennsylvania