Plasmalogen-based therapeutic strategy for the treatment of Hereditary Spastic Paraplegia

Hereditary Spastic Paraplegias (HSPs) are inherited neurologic disorders characterized by high genetic heterogeneity. Nevertheless, alterations in morphology or distribution of the endoplasmic reticulum (ER) appears to be a critical pathogenic factor. Recently, a novel mutation in EPT1 gene, encoding a crucial enzyme in the biosynthesis of plasmalogens (PLs), was identified in HSP patients. PLs are ether phospholipids abundant in ER membranes. Ethanolamine-based PLs (PE-PLs) are enriched in nervous system membranes, constituting up to 85 mol% of total phosphatidylethanolamine (PE) species and up to 30 mol% of total phospholipids in mammalian brains. Notably, PLs amount was found decreased in several neurological diseases, suggesting that PLs could play a role in neuronal membranes welfare. PE-PLs are suggested to promote the formation of inverted hexagonal phases, thus facilitating membrane fusion events, however, the sub-molecular details behind the above properties are not fully understood. By exploiting in vitro, in situ and in vivo (Drosophila melanogaster) HSP models, we aim at identifying a potential role for PLs in the remodeling of ER membranes in neurons. Our hypothesis is that manipulating ER membrane lipid composition in a way that favors membrane dynamics, we could rescue HSP-related ER morphology defects. The validated approach could prove a new therapeutic option for HSPs and potentially for other neurodegenerative diseases involving phospholipids-related membrane impairment.