A Patient-Derived Stem Cell Model of Hereditary Spastic Paraplegia with SPAST mutations
Author(s)
Primary Supervisor
Crane, Denis
Mackay-Sim, Alan
Other Supervisors
Fan, Yongjun
Year published
2016
Metadata
Show full item recordAbstract
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 ...
View more >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.
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View more >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.
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Thesis Type
Thesis (PhD Doctorate)
Degree Program
Doctor of Philosophy (PhD)
School
School of Natural Sciences
Copyright Statement
The author owns the copyright in this thesis, unless stated otherwise.
Item Access Status
Public
Subject
Stem cell model
Hereditary spastic paraplegia