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Title: Molecular pathomechanisms of Amyotrophic Lateral Sclerosis caused by FUS mutations
Author: An, Haiyan
ISNI:       0000 0004 8500 8668
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2019
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Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease affecting both upper and lower motor neurons. About 10% of ALS cases run in families with known genetic background, and mutations in the Fused in Sarcoma (FUS) gene are responsible for about 5% of the fALS cases (ALS-FUS). Despite normal FUS is a predominantly nuclear protein, mutant FUS is found to accumulate and aggregate in the cytoplasm of affected neurons and glial cells in ALS-FUS. It is generally believed that mutations are the primary cause of FUS protein mislocalisation, and additional stresses are required to trigger the formation of insoluble FUS aggregates (FUSopathy). However, no clear consensus has been achieved on many important questions. For instance, what are the consequences of FUS protein mutation for its nuclear function and how do they contribute to ALS-FUS development? What is the nature of the stress that promotes the massive protein accumulation and inclusion formation in the cytoplasm? This thesis attempts to address these questions using novel cellular models with targeted modifications of the FUS gene. It is demonstrated that the presence of endogenous mutant FUS protein in the nucleus causes hyper-assembly of structurally and functionally abnormal paraspeckles - nuclear bodies assembled on the long non-coding RNA called Nuclear Paraspeckle Assembly Transcript 1 (NEAT1). Dysfunctional paraspeckles together with accumulation of NEAT1 outside paraspeckles might contribute to the disease severity. Stresses capable of triggering cytoplasmic FUS aggregates are also investigated, and as a result, antiviral immune response has emerged as a potent stress promoting formation of persistent cytoplasmic FUS-positive assemblies. In addition, type I interferon expressed during antiviral response is found to cause FUS protein accumulation by increasing FUS mRNA stability. I propose a multi-step model where antiviral immune response serves as the "second hit" provoking FUSopathy. This thesis offers novel insights into the cellular and molecular events leading to the initiation and progression of ALS-FUS, which should help inform the development of therapeutic strategies in the future.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available