Uncovering the role of ER-shaping proteins in neurodegenerative disease

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterised by degeneration of the longest motor neurons which leads to muscle weakness and spasticity in the lower limbs. There are currently no treatments to cure or even to slow the course of these diseases.

We aim to determine the molecular mechanisms by which disease-causing variants give rise to neurodegeneration in HSP. We will generate the world’s first in vivo models of HSP which endogenously express patient-specific gene variants via CRISPR-Cas9 gene editing in Drosophila. By integrating disparate genetic, proteomic and imaging analyses of these novel models, we will identify how HSP-causing variants alter protein expression, localisation and interaction. We will then establish the clinical relevance of identified mechanisms by studying disease-causing variants in human cellular models of HSP.

The findings from fly and human models of HSP will greatly enhance our understanding of the molecular mechanisms underpinning these neurodegenerative disorders. The models we generate will provide valuable investigative resources for studying the cellular events underlying neurodegenerative disease and a new method for screening therapeutic approaches for these degenerative disorders.