Unravelling Molecular Mechanisms of ALS: Characterizing the in vitro and in vivo effects of biometals on the ALS-linked proteins TDP-43, SOD1, PGRN, and MFSD8
Project Overview
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, typically resulting from gene mutations that facilitate abnormal protein aggregation. Studies suggest that mutations in several proteins including TDP-43, SOD1, PGRN, and MFSD8, are linked to familial and sporadic cases of ALS (fALS/sALS). In each protein, mutations differ not only in global populations, but also in geographically proximal regions, with studies showing that identical mutations can have highly variable clinical phenotypes. Studies on ALS pathology are often focused on protein-protein interactions and the inhibition of intrinsically disordered proteins. However, recent work highlights the role of biometals in regulating the structure and function of protein associated with ALS, as well as the impact of metal dysregulation on ALS development and progression. Our research aims to characterize the in vitro coordination of biometals with proteins linked to ALS using high resolution tandem mass spectrometry, as well as investigating protein stability and fragmentation in metal-bound complexes. Additionally, using the single-cell amoeba model organism (Dictyostelium discoideum), we aim to build on current ALS-associated gene homologue characterizations, specifically human PGRN/CLN11, where phenotypic and behavioural effects during cell development will be determined. We propose expressing human ALS-associated proteins, including TDP-43, in this model organism to characterize their cytotoxic effects and to assess their influence on biometal regulation. These approaches will help us understand if ALS genes are involved in metal dysregulation and potentially act as biomarkers for disease detection for the development of ALS therapeutic strategies.
Principal Investigator
Josephine Esposto , Trent University
Partners and Donors
Allan Kliger, Aviva Rajsky & Family