Study Rationale:
Parkin is a protein made by all cells in the body, including brain cells. It plays an important role in the protection of neurons through a process known as quality control. Changes (mutations) in parkin that impair its function are known to cause early-onset parkinsonism, an inherited form of Parkinson's disease (PD). Restoring the function of parkin could slow or even stop the progression of all types of PD.
Hypothesis:
We hypothesize that the activation of parkin with small-molecule drugs could treat PD.
Study Design:
First, using computational methods, we will determine which regions (parts) of parkin are responsible for its activation. After the selection of the region most likely to activate parkin, a combination of mathematical and experimental methods will be used to identify small molecules that may bind to this promising region. The search for such molecules will take advantage of a new technology that empowers researchers with artificial intelligence to maximize the success of finding small-molecule activators of parkin.
Impact on Diagnosis/Treatment of Parkinson's Disease:
The small molecules identified in this study may be used to design new drugs for PD. As no existing or prospective drug modifies the activity of parkin, a new class of therapeutics could be developed. Additionally, such therapeutics could be useful in studying the role of parkin activation in Parkinson's disease.
Next Steps for Development:
The identified small molecules that activate parkin should serve as a starting point for drug discovery and development. This would allow the small molecules to be further optimized by improving their pharmacological properties and ability to activate parkin.