Summary: Researchers identified LIPE, a lipase that degrades triglycerides to produce fatty acids, as a potential new target for the development of treatments for Parkinson’s disease.
Source: Brigham and Women’s Hospital
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.”
Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy
Synucleinopathy (Parkinson’s disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. Although the PD-causing protein α-synuclein (αS) interacts with lipids and fatty acids (FA) physiologically and pathologically, targeting FA homeostasis for therapeutics is in its infancy.
We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. However, lipid degradation also generates FA pools.
Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. Decreasing LIPE in human neural cells reduced αS inclusions. Patient αS triplication vs. corrected neurons had increased pSer129 and insoluble αS and decreased αS tetramer:monomer ratios.
LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in αS E46K-expressing human neurons. LIPE reduction in vivo alleviated αS-induced dopaminergic neurodegeneration in Caenorhabditis elegant.
Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy.