A.I.Vi.P.S 2021 - Microtubule cytoskeleton organization as biomarker to develop new therapeutic perspectives for Hereditary Spastic Paraplegia type 4 (HSP-SPG4) (DSB.AD006.323)
Area tematica
Area progettuale
Biologia Molecolare/Cellulare (DSB.AD006)Struttura responsabile del progetto di ricerca
Istituto di biologia e patologia molecolari (IBPM)
Responsabile di progetto
FRANCESCA SARDINA
Telefono: 0649917537
E-mail: francesca.sardina3@gmail.com
Abstract
The most common type of HSP is due to heterozygous loss of function mutations in the SPG4 gene, coding the microtubule (MT) severing enzyme spastin. To date there is no cure and SPG4-HSP progression is unpredictable, even in the same family. Innovative preclinical treatment strategies with therapeutic potential are emerging. Thus, there is an urgent need both for prognostic and predictive biomarkers. Recently, we showed rescue of neurite defects by pharmacologically elevating spastin levels in cells recapitulating SPG4-HSP defects. We observed peculiar MT network defects in SPG4 lymphoblastoid cell lines (LCLs) that were rescued by pharmacologically elevating spastin levels. Here, I propose to deeply characterize MT network organization in LCLs from SPG4-HSP patient families, in order to establish a correlation between the observed defects and the severity of the disease. Additionally, I will characterize MT network organization in response to spastin elevating approaches. The main goals of this proposal will be to obtain a prognostic test for SPG4-HSP and to set up an experimental system to predict the effectiveness of therapeutic treatments.
Obiettivi
The focus of this proposal is to develop new non-invasive tools for SPG4-HSP prognosis and treatment, capitalizing on our preliminary findings indicating that SPG4 patient's derived cells show distinctive MT cytoskeleton defects, that are rescued by MNL4924-induced spastin restoration treatment (see below preliminary work). We will,
1. characterize a poorly understood aspect of SPG4-HSP disease, evaluating if difference on MT cytoskeleton network architecture in different patients correlate with molecular and clinical features.
2. analyze the MT cytoskeleton network architecture of SPG4-HSP cells in response to spastin elevating approaches.
Data inizio attività
01/05/2021
Parole chiave
microtubules, spastin, Hereditary Spastic Paraplegia
Ultimo aggiornamento: 28/03/2024