Study Rationale: Parkinson’s disease (PD) is characterized by an abnormal accumulation of alpha-synuclein. One of this protein’s normal functions involves binding to fatty acids and lipids, and numerous studies show that lipids and fatty acids are altered in the brain, cerebrospinal fluid and plasma of people with PD. These observations suggest that interactions between lipids and alpha-synuclein are physiologically and pathogenically important. We have shown that the presence of excess or mutant alpha-synuclein induces an imbalance in lipid and fatty acids. Modulating specific lipid pathways could therefore slow the pathology initiated by the buildup of abnormal alpha-synuclein aggregates.
Hypothesis: We hypothesize that alpha-synuclein’s interactions with lipids and fatty acids could provide targets for the development of new therapeutics for the treatment of PD.
Study Design: In this study, we will explore the effect that modifying cellular lipids and fatty acids has on alpha-synuclein biology in neurons derived from people with PD as well as preclinical PD models. We will determine how perturbing alpha-synuclein alters the profile of neuronal lipids and assess whether candidate therapeutic interventions will restore lipid balance. In particular, our previous work identified stearoyl-CoA-desaturase—an enzyme involved in lipid synthesis—as a candidate PD drug target. An inhibitor of this enzyme is now in clinical trials for PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: Several studies have associated genes related to lipid/fatty acid balance with PD, making these pathways attractive targets for the development of new PD therapeutics.
Next Steps for Development:
If this study is successful, the next steps will include assessing candidate drugs for their ability to cross the blood-brain barrier and performing additional analyses in preclinical models in preparation for progression to human trials.