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Cellular Pathomechanisms in Hereditary Sensory Neuropathy Type 1

Wilson, Emma Rachel; (2017) Cellular Pathomechanisms in Hereditary Sensory Neuropathy Type 1. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by missense mutations in the SPTLC1 or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase (SPT). SPT catalyzes the first and rate-limiting step of de novo sphingolipid synthesis. Mutations in SPT result in a change in enzyme substrate specificity, which generates two atypical products, deoxysphinganine and deoxymethylsphinganine, rather than the normal enzyme product, sphinganine. Levels of these abnormal compounds are elevated in the blood of HSN-1 patients and this is thought to cause the peripheral sensory and motor nerve damage characteristic of the disease. However, the mechanisms underlying nerve damage are largely unresolved and there remain no effective treatments. In this study, the cellular pathomechanisms that underlie the peripheral nerve damage in HSN-1 were examined using three in vitro models of disease. Firstly, primary motor and sensory neurons from wildtype mice were treated with either the typical enzyme product, sphinganine, or the atypical enzyme products, deoxysphinganine and deoxymethylsphinganine. The abnormal enzyme products were found to have dose- and time- dependent neurotoxic effects in both motor and sensory neurons. In addition, functional analyses revealed that the deleterious effects of the abnormal enzyme products may be mediated, at least in part, by abnormal calcium handling and mitochondrial dysfunction. In order to further explore the disease pathomechanisms and confirm whether these deficits were also present in models that more closely resemble the genetic aspect of this disease, two additional in vitro models were examined. In the first of these models, a lentiviral vector was generated in order to deliver wildtype and mutant SPTLC1 to primary motor and sensory neurons, and in the second, control and HSN-1 patient fibroblasts were obtained and examined. The results of this Thesis suggest that alterations in mitochondrial function and cellular calcium handling may contribute to the pathomechanism of HSN-1, and may therefore represent a potential target for therapeutic development.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Cellular Pathomechanisms in Hereditary Sensory Neuropathy Type 1
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Third party copyright material has been removed from ethesis.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10037613
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