Adom_2024_Neurobiol.Dis__106593

Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and can shift the physiological alpha-synuclein (alphaS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ alphaS monomers associating with excess mono- and polyunsaturated fatty acids contributes to the alphaS aggregation. We previously reported that decreasing the release of monounsaturated fatty acids (MUFAs) by reducing or inhibiting the hormone sensitive lipase (LIPE) reversed pathologic alphaS phosphorylation and improved soluble alphaS homeostasis in cultured alphaS triplication PD neurons and reduced DAergic neurodegeneration in a C.elegans alphaS model. However, assessing LIPE as a potential therapeutic target for progressive PD motor phenotypes has not been investigated. 3 K alphaS mice, representing a biochemical and neuropathological amplification of the E46K fPD-causing mutation, have decreased alphaS T:M ratios, lipidic aggregates, and a L-DOPA responsive PD-like motor syndrome. Here, we reduced LIPE by crossings of 3 K mice with LIPE null mice, which attenuated motor deficits in male LIPE(+/-) knockdown (LKD)-3 K mice. Heterozygous LIPE reduction was associated with an improved alphaS T:M ratio, and dopaminergic neurotransmitter levels and fiber densities. In female 3 K-LKD mice, an increase in pS129+ and larger lipid droplets (LDs) likely decreased the benefits seen in males. Reducing LIPE decreased MUFA release from neutral lipid storage, thereby reducing MUFA in phospholipid membranes with which alphaS interacts. Our study highlights fatty acid turnover as a therapeutic target for Lewy body diseases and support LIPE as a promising target in males. LIPE regulation represents a novel approach to mitigate PD and DLB risk and treat disease.