Lipid droplets in neurodegenerative diseases: pathological drivers and therapeutic vulnerabilities.

Lipid droplets (LDs) are dynamic intracellular organelles traditionally associated with energy storage, which have become increasingly recognised for their versatile roles in cellular metabolism and signalling. In the brain, LDs have emerged as critical regulators in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Hereditary Spastic Paraplegia (HSP). LDs contribute to neurodegeneration by influencing lipid metabolism, oxidative stress, and inflammatory responses. For instance, in AD, dysregulated lipid metabolism and impaired Apolipoprotein E 4 (ApoE4) function lead to LD accumulation associated with neuroinflammation and amyloid plaque formation. In PD, interactions between LDs and α-synuclein suggest a potential link between lipid dysregulation and neurotoxicity. Mutations in LD-associated proteins, such as spastin and DDH2 in HSP, highlight the importance of proper LD regulation for neuronal health. While LD accumulation can be protective by mitigating lipotoxicity, prolonged dysregulation can exacerbate NDD pathology. Targeting LD metabolism, through enhancing lipophagy or modulating LD-associated proteins, represents a promising therapeutic avenue. This review highlights the dual roles of LDs in the brain, acting both neuroprotectively and neurotoxically, and the therapeutic potential of targeting LD dynamics for NDD treatment.