TELETHON GRANT PROJECT 2019 N. GGP19304 - DR.SSA DIANA PENDIN - PLASMALOGEN-BASED THERAPEUTIC STRATEGY FOR THE TREATMENT OF EREDITARY SPASTIC PARAPLEGIA (DSB.AD004.268)

Area tematica

Scienze biomediche

Area progettuale

Struttura responsabile del progetto di ricerca

Istituto di neuroscienze (IN)

Responsabile di progetto

DIANA PENDIN
Telefono: 049/8276043
E-mail: diana.pendin@cnr.it

Abstract

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 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 mem

Obiettivi

We aim at identifying a potential new therapeutic approach for HSPs, able to restore the membrane dynamics alterations reported for at least a subset of HSP proteins. We will exploit HSP fly models due to deficiency of membrane shaping proteins (atlastin, Rtnl1) or lipid metabolism enzymes (EPT1). Our results will clarify whether distinct pathogenic mechanism can be treated focusing on a single, convergent aspect, i.e. membrane dynamics. Selected PLs precursors will be administered to flies and lipidomic analysis of samples collected will allow to identify the most effective treatment in increasing ER membrane PLs. The results we will obtain will provide the basis for future clinical trials, aimed at increasing membrane PLs concentration in HSP patients upon oral administration.

Data inizio attività

01/11/2019

Parole chiave

: Endoplasmic Reticulum, Hereditary Spastic Paraplegia, Intracellular Membranes

Ultimo aggiornamento: 16/04/2025