Abramzon, Yevgeniya;
(2022)
Genetics of amyotrophic lateral sclerosis and frontotemporal dementia and the potential for discovering new genes and pathways underlying these neurological disorders.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Despite tremendous progress in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) genetic research over the last two decades, only 20% to 40% of the underlying genetic causes have been discovered. Several genes responsible for these two neurological disorders remain to be discovered. During my Ph.D., I utilized the current state-of-the-art exome and whole-genome sequencing technologies to discover new loci underlying ALS and FTD. This genetic knowledge helps to unravel the complex etiology of these disorders and paves the way for targeted therapies. Chapter 1 of this thesis talks about the evolution of genetic research in the past two decades. Chapter 2 introduces ALS and FTD, the two neurological disorders that are the focus of my thesis. Chapter 3 provides an overview of the genetics of ALS and FTD. Chapter 4 describes the discovery of the new gene linked to juvenile ALS, serine palmitoyltransferase long chain subunit 1 (SPTLC1), and proposes a treatment for the patients carrying mutations in this gene. Chapter 5 demonstrates that exome sequencing is a powerful technique for the analysis of rare hereditary conditions. I describe the discovery of gelsolin p.D187Y amino acid change, which was previously linked to hereditary amyloidosis type 4, in a large family in which multiple members were affected by bulbar neuropathy mimicking bulbar ALS. Chapter 6 discusses the role of the highly polymorphic locus replication factor C subunit 1 (RFC1) in ALS. Chapter 7 describes our whole-genome sequencing efforts in dementia and examines the data for the frequency of intermediate-size repeat expansions in genes previously linked to neurodegeneration.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Genetics of amyotrophic lateral sclerosis and frontotemporal dementia and the potential for discovering new genes and pathways underlying these neurological disorders |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10145246 |
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