The human brain is lipid rich. Lipids and fatty acids contribute to many important cellular processes. Alpha-synuclein — a protein that plays a critical role in Parkinson’s disease (PD) — is known to interact with and alter the balance of lipids and fatty acids. Investigators from the Brigham and Harvard Medical School are exploring how to rebalance fatty acid metabolism in the brain to find new therapeutic approaches for PD and related conditions. Their previous work has led to the identification of an inhibitor of an enzyme called stearoyl-CoA-desaturase, which is now being tested in human clinical trials. In a new study, they identify LIPE, a lipase that degrades triglycerides to produce fatty acids, as a candidate therapeutic target. Inhibiting LIPE reduced the formation of clusters of α-synuclein inclusions and other characteristics associated with PD in patient-derived neurons. LIPE reduction also alleviated neurodegeneration in a C. elegans model of α-synuclein toxicity.
“Our research led us to become increasingly aware of the role lipid and fatty acid balance may play in Parkinson’s disease,” said co-corresponding author Saranna Fanning, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham. “Ultimately, we hope this lipid-related target will have promise as a small-molecule therapy for Parkinson’s disease.”
Co-corresponding author Dennis Selkoe, MD, also of the Ann Romney Center for Neurologic Diseases at the Brigham, added, “The identification of LIPE inhibition and a unique co-regulation of fatty acid synthesis and degradation pathways are further evidence that targeting fatty acid metabolism holds promise for Parkinson’s disease.”
Read more in npj-Parkinson Disease.
npj Parkinson s Disease
Experimental study
Human tissue samples
Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy
9-Jun-2022
D.S. is a director and consultant to Prothena Biosciences. All other authors declare no competing financial or non-financial interests.