A Patient-Derived Stem Cell Model of Hereditary Spastic Paraplegia with SPAST mutations

Abstract

Hereditary spastic paraplegia (HSP) is an inherited neurological disorder characterised by degeneration of long axons along the corticospinal tract, leading to lower limb spasticity and gait abnormalities. The mechanisms underlying HSP mutations that lead to degeneration of the long axons are unclear. Mutations in the SPAST gene account for the largest group of adult-onset HSP patients. In this thesis, I evaluated olfactory-neurosphere derived (ONS) cells, a population of neural progenitor cells, derived from biopsies of the olfactory mucosa from HSP patients and from healthy controls, in order to identify cell functions altered in HSP. The patient donors carried different SPAST mutations that included c.1413+3_1413+6del, p.E464D; c.1392 A>T, p.L195V; c.583C>G, p.E366K); c.1096G>A. SPAST encodes for spastin, a microtubule severing protein. Previous work has shown that patient ONS cells have reduced levels of spastin, dysregulation in gene expression of genes associated with microtubule dynamics, reduced levels of acetylated -tubulin (a measure of stable microtubules) and abnormal intracellular distribution of peroxisomes and mitochondria.