Summary: Researchers have identified LIPE, a triglyceride-degrading lipase that releases fatty acids, as a promising new target for developing Parkinson’s disease therapies.
Source: Brigham and Women’s Hospital
The human brain is rich in lipids. Lipids and fatty acids are integral to membrane structure, signaling, energy balance and many cellular processes. Alpha-synuclein, a protein centrally involved in Parkinson’s disease (PD), interacts with lipids and influences fatty acid balance, and these interactions are believed to affect disease progression.
Investigators at Brigham and Women’s Hospital and Harvard Medical School have been studying how to rebalance fatty acid metabolism in the brain as a route to new therapies for Parkinson’s disease and related synucleinopathies. Their prior work led to the discovery of an inhibitor of stearoyl-CoA desaturase, an enzyme that regulates monounsaturated fatty acid synthesis; that inhibitor is now being tested in human clinical trials.
In a new study, the research team shifts focus to lipid breakdown and identifies LIPE, a rate-limiting lipase that liberates fatty acids from triglycerides, as a candidate therapeutic target. The study shows that reducing LIPE activity can counteract several cellular and animal-model features linked to alpha-synuclein toxicity.
In human neurons derived from patients, pharmacological or genetic inhibition of LIPE decreased the formation of clustered alpha-synuclein inclusions and reduced biochemical markers associated with Parkinson’s pathology. Specifically, LIPE suppression lowered levels of phosphorylated alpha-synuclein at serine 129 (pSer129), normalized the balance between tetrameric and monomeric forms of alpha-synuclein, and ameliorated signs of an abnormal unfolded protein response. Complementing these cellular results, reducing LIPE in a Caenorhabditis elegans model of alpha-synuclein toxicity lessened dopaminergic neuron degeneration.
The authors also compared neurons carrying an alpha-synuclein gene triplication—an established genetic cause of familial PD—with corrected control neurons. Triplication neurons showed increased insoluble alpha-synuclein and pSer129 alongside a disrupted tetramer:monomer equilibrium; LIPE inhibition helped restore these measures toward normal. In neurons expressing the pathogenic E46K alpha-synuclein variant, LIPE inhibitors similarly decreased pSer129 and restored tetramer:monomer balance.
Importantly, the study highlights that targeting both sides of fatty acid homeostasis—synthesis and degradation—can be additive. Co-regulating enzymes that make fatty acids and enzymes that break them down produced stronger rescue of Parkinson’s-related phenotypes than targeting either pathway alone, suggesting a combined therapeutic approach may be effective.
“Our research emphasized the significance of lipid and fatty acid balance in Parkinson’s disease,” said co-corresponding author Saranna Fanning, PhD, of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital. “We hope focusing on lipid-related targets like LIPE will open the door to small-molecule therapies that can modify disease processes.”
Co-corresponding author Dennis Selkoe, MD, also of the Ann Romney Center, added, “The identification of LIPE inhibition and the observed coordination between fatty acid synthesis and degradation pathways reinforce the idea that manipulating fatty acid metabolism has therapeutic potential in Parkinson’s disease.”
These findings add to emerging evidence that lipid metabolism—and especially the balance between fatty acid production and degradation—plays a pivotal role in synucleinopathy pathogenesis. By pinpointing LIPE as a modulator of fatty acid pools and alpha-synuclein behavior, the study provides a clear experimental rationale for developing LIPE-directed compounds and for exploring combined strategies that adjust both synthesis and breakdown of fatty acids.
About this Parkinson’s disease research news
Author: Haley Bridger
Source: Brigham and Women’s Hospital
Contact: Haley Bridger – Brigham and Women’s Hospital
Image: The image is in the public domain
Original Research: Open access. “Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy” by Saranna Fanning et al., npj Parkinson’s Disease
Abstract
Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy
Synucleinopathies, including Parkinson’s disease and Lewy body dementia, represent an urgent unmet medical need for disease-modifying treatments. Alpha-synuclein interacts with lipids and fatty acids in both normal and disease states, but therapeutic strategies that target fatty acid homeostasis remain in early stages of development.
Previously, the team identified stearoyl-CoA desaturase as a PD-relevant target, where inhibiting monounsaturated fatty acid synthesis reversed disease-related phenotypes. Recognizing that lipid degradation also creates pools of fatty acids, the investigators examined whether targeting lipolytic enzymes could likewise influence alpha-synuclein pathology.
They identified LIPE as a rate-limiting lipase and candidate therapeutic target. Lowering LIPE levels in human neural cells reduced alpha-synuclein inclusions and corrected biochemical abnormalities seen in patient-derived neurons, including pSer129 elevation and disturbed tetramer:monomer ratios. LIPE inhibition also improved the unfolded protein response and reduced toxicity in models expressing pathogenic alpha-synuclein variants. In vivo reduction of LIPE alleviated alpha-synuclein–induced dopaminergic neuron degeneration in Caenorhabditis elegans. Co-targeting fatty acid synthesis and degradation produced additive benefits, supporting a combined metabolic approach as a potential therapeutic strategy.