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Title: Age-related changes affect human astrocyte function and have important implications for the function of SOD1 and its role in amyotrophic lateral sclerosis (ALS)
Author: Gatto, Noemi
ISNI:       0000 0004 9358 2483
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2020
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ALS is a fatal neurodegenerative disorder, partly understood through studies on the first gene associated with familial ALS (fALS), SOD1. Several pieces of evidence indicate that misfolded wild-type SOD1 may also play a role in the pathophysiology of sporadic ALS (sALS), through different processes, such as misfolding, aggregation and prion-like pathogenic behaviour. Moreover, there is evidence indicating that SOD1 could function as a transcription factor. The main risk factor for ALS is ageing; ageing and neurodegeneration share several pathways. Remarkably, it has been demonstrated that glial cells change their gene expression dramatically during physiological brain ageing. Thus, it is important to have these cells suitable for disease modelling, especially in neurodegenerative diseases like ALS, in which astrocytes actively contribute to motor neuron death. In my study, directly derived astrocytes from young and old donor fibroblasts preserve ageing signatures, representing a valuable model to study astrocytic function. To study the effect of wild-type SOD1 in fALS and sALS, induced astrocytes from control and patient fibroblasts were also generated. Staining for misfolded SOD1 showed nuclear aggregation of the protein in sALS astrocytes. This poses a question on the role of SOD1 in this cellular compartment. The nuclear presence of SOD1 in patient astrocytes was confirmed via cell fractionation, indicating that SOD1 might indeed act as a transcription factor or a co-activator. Furthermore, exportin-1 (XPO1) is able to shuttle misfolded SOD1 to the cytoplasm as a defence mechanism against toxicity. My data show that the expression levels of this protein naturally decrease with age. Its levels further decrease in sALS patients compared to controls, consistent with the finding of accumulation of misfolded SOD1 in the nucleus. I confirmed the interaction between XPO1-SOD1 through a proximity ligation assay. Moreover, a decrease in the interaction between XPO1 and misfolded SOD1 was detected in sALS and C9orf72 ALS cases, in agreement with the higher levels of nuclear SOD1 observed in these ALS patient subgroups.
Supervisor: Ferraiuolo, Laura ; Shaw, Pamela Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available