Stimulating autophagy to improve intracellular proteostasis in MND

Motor neuron disease (MND) is a protein misfolding disorder linked to defects in proteostasis pathways, or protein homeostasis, within affected neurons.

MND is associated with cytoplasmic accumulation and aggregation of misfolded proteins, notably SOD1, TDP-43, FUS and C9ORF72 dipeptide repeat proteins, which are implicated in neuronal stress and death.  Strategies that improve intracellular proteostasis and clear these misfolded proteins in motor neurons may therefore offer a rational approach to improve neuronal health and potential outcome in MND.

Our group focuses on autophagy, the main catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles by bulk or selective targeting of these substrates to lysosomes for digestion.

This project will investigate the therapeutic effects and action of stimulating autophagy in genetic cell culture and mouse models of MND.  The effects of newly identified autophagy stimulating agents will be evaluated on clinical progression, neuropathology and misfolded and aggregated protein load in the central nervous system of mouse models of MND.

Reference:

Perera ND, Sheean RK, Lau CL, Shin YS, Beart PM, Horne MK, Turner BJ (2017) Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression. Autophagy.