Meredith Jackrel, Ph.D.
Project Overview:
Proteins serve numerous functions essential for our health. In many neurodegenerative disorders, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), specific proteins clump up in patients’ brains. These clumps can cause disease by preventing the specific proteins from performing their normal functions, or the clumps might block cellular processes. These disorders are widespread and severely debilitating, significantly shortening lifespan 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 AD. This discovery suggests that HtrA1 might normally defend the brain from 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 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, most notably ALS (Lou Gehrig’s disease) and PD. These studies will enable us to validate HtrA1 and its upregulation as a valid therapeutic target, paving the way for our 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.
Progress Report:
Treatments for protein-misfolding disorders are severely limited and fail to combat their underlying cause: protein aggregation. Novel therapies for these disorders are crucial, as they are severely debilitating, significantly shortening lifespan and decreasing quality of life. Recent discoveries suggest that protein disaggregases may be defenders against misfolding. We aim to bolster these defenses in order to combat misfolding. In the first year of this grant we acquired compelling data suggesting that HtrA1 colocalizes with, and presumably remodels, α-syn. We also isolated two lead enhanced variants. We propose to continue this work in order to comprehensively define the activity of HtrA1 against different substrates in order to provide evidence validating HtrA1 as a viable therapeutic target. Furthermore, we will comprehensively characterize the lead variants to demonstrate that they can remodel these substrates and reverse disease phenotypes. These enhanced variants might have therapeutic value themselves and could be delivered via gene therapy or direct injection. By reactivating misfolded species, HtrA1 could simultaneously counter a loss or toxic gain of function mechanism. We will also test the efficacy of these agents in mammalian neurons to demonstrate that they can dissolve aggregates and reverse disease pathology. Completion of this project will give us strong preliminary data to apply for future funding.
In these future studies, we will forge collaborations to assess the activity of the variants in different animal models. Our membership and ongoing interactions with fellow labs in the Hope Center for Neurological Disorders – Washington University in St. Louis School of Medicine will greatly empower these efforts. Additionally, we plan to conduct screens for small molecule modulators that boost HtrA1 activity, because small molecules might have a more straightforward pathway to human use. While the timeline for bringing a drug to patients can be quite long, I anticipate that within this award period we can validate HtrA1 as a therapeutic target and gain new insights into how best to attack ALS, PD, and other disorders.
