Restoring proteostasis to counter human disease
Proteins serve numerous functions essential for our health. In many neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease, specific proteins clump in patients’ brains. These clumps can cause disease by preventing these proteins from performing their normal functions. The clumps can also block cellular processes. These disorders are widespread and severely debilitating, significantly shortening lifespans and decreasing quality of life. However, despite intense efforts, there are no effective treatments for any of these disorders.
An attractive therapeutic strategy would be to develop agents capable of not simply destroying the clumps, but restoring the proteins back to their normal shapes and functions. However, these clumps are extremely resistant to elimination.
It was recently discovered that humans have a protein called HtrA1 that can dissolve the clumps implicated in Alzheimer’s disease (AD). This discovery suggests that HtrA1 might be a protein that normally defends the brain from the onset of AD, but is prone to failure as we age. Furthermore, it is plausible that HtrA1 might control a natural defense mechanism that preserves general brain health by preventing protein clumping in the brain. In this proposal, we seek to define the roles of HtrA1 in preventing the clumping of many different proteins in many disorders. We will then develop approaches to modify HtrA1 to enhance its activity so that it can combat AD and other disorders. These studies will enable us to validate HtrA1 and its upregulation as a valid therapeutic target, paving the way for future work to develop small molecules that might be used as drugs to boost natural defense mechanisms to prevent and reverse protein clumping in the brain.