Millions currently suffer from Alzheimer's disease (AD); as life expectancy increases, it will become increasingly widespread. AD results from the degeneration and death of neurons of the hippocampus and entorhinal cortex. End stage patients require continuous care, and AD is currently the sixth leading cause of death in the U.S. There is currently no cure; approved treatments, aimed at improving cognition and slowing progression, focus primarily on increasing the level of acetylcholine in the brain. Such treatments, which have serious side effects and relieve AD symptoms only for a limited time, cannot prevent neuronal death. Thus, an urgent need exists to identify novel agents that prevent AD progression by acting on targets that mediate neuronal death. The mitochondrion is such a target; excess dysfunctional mitochondria in AD-linked neurons lower energy efficiency and release reactive oxygen species contributing to neuronal death. The dysfunctional mitochondria are cleared by phosphorylation and ubiquitin-mediated autophagy (mitophagy), or degradation in auto phagosomes. The ubiquitin pathway component consists of the conjugating enzyme parkin, which tags defective mitochondria with ubiquitin for removal, and the deubiquitinating enzyme USP30, which deconjugates ubiquitin, preventing the removal of defective mitochondria. Normally, in AD patients the ability to clear defective mitochondria is overwhelmed, and replacement of parkin function by overexpression can rescue AD symptoms in vivo. Moreover, USP30 knockout has been shown to enhance parkin activity and increase mitochondrial integrity in neurons. These findings lead to the hypothesis that USP30 is a novel target for developing small molecule inhibitors for treatment of AD; USP30 inhibitors are expected to prevent mitophagy deficiency-induced neuronal death, thereby hindering progression of AD. It is proposed to identify novel modulators of USP30 by screening a diverse collection of small molecules. An enzymatic-based USP30 assay for high throughput screening (HTS) will be configured and Progenra's 220,000 compound collection will be screened. Confirmed hits will be reordered, along with a subset of related analogs, and profiled against a series of DUBs and other proteases before initiating a hit to lead optimization program. The most promising compounds from this program will be examined in cellular models of mitophagy rescue. In phase II, the most interesting compounds will be progressed to hit-to-lead medicinal chemistry optimization with associated DMPK and additional cellular and animal model studies. The commercial goal is a novel drug to treat AD.

Public Health Relevance

Alzheimer's disease (AD) is devastating in terms of mortality, morbidity, emotional strain, and cost. There is currently no cure; approved treatments address symptoms but lose efficacy over time and do not prevent neuronal death, the root cause of the disease. In the proposed project, inhibitors of a newly discovered enzyme from the ubiquitin pathway which helps to maintain neuronal cell death will be identified and tested for their ability to stop the progression of symptoms of AD in an animal model. Appropriate inhibitors will be developed as novel treatments for AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Refolo, Lorenzo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Progenra, Inc.
United States
Zip Code