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Use of the spastin mouse model to suggest novel approaches for the treatment of hereditary spastic paraplegia

Mehdar, Khlood (2017) Use of the spastin mouse model to suggest novel approaches for the treatment of hereditary spastic paraplegia. PhD thesis, University of Sheffield.

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Hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurological disorders that are characterised by lower limb spasticity and weakness. Their clinical pathophysiology is degeneration of the corticospinal tract. The most common HSP gene is spastin (SPAST). SPAST encodes a microtubule severing protein. Mutations in SPAST cause reductions in axonal transport that lead to axonal swellings in the corticospinal tract with mitochondrial accumulation. Finding a therapy for HSP is challenging. In this thesis I tested different therapeutic approaches using a spastin mouse model. To alleviate symptoms of HSP, physicians recommend taking a low level of regular exercise, but these recommendations are not based on any formal evidence. Therefore, I used the spastin mouse to investigate whether or not regular exercise on a home cage running wheel modifies the development of progressive gait defects. I found that exercise reduced the progression of the gait defect and also reduced the number of axonal swellings in the spinal cord. Microtubule acetylation has been shown to regulate axonal transport. Increased acetylation by chemical inhibition of histone deacetylase 6 (HDAC6) has been shown to be neuroprotective. I used a combination of pharmacological and genetic inhibition of HDAC6 in a spastin mutant mouse model to determine whether HDAC6 is a valid target for therapeutic intervention in HSP. My results suggest HDAC6 inhibition may be useful in alleviating pathological axonal swellings, but had no beneficial effect on gait. Microtubule stabilising agents are another approach for the treatment of neurodegenerative disease, since these have been shown to modify axonal transport defects. Among MTs stabilisers, Epothilone D (EpoD) which is able to penetrate the blood brain barrier. Treating spastin mice with EpoD showed no beneficial effect on gait, and in fact tended to worsen the axonal swelling pathology. Although neither the reduction nor increase in the number of axonal swellings modified the gait defect. We concluded that there is no relationship between the axonal swellings in the spinal cord and the gait defect in spastin mouse model of HSP.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: Mrs Khlood Mehdar
Date Deposited: 08 May 2018 09:19
Last Modified: 08 May 2018 09:19
URI: http://etheses.whiterose.ac.uk/id/eprint/19814

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