Taha, Doaa Marei Abdallah; (2022) Examining molecular mechanisms underlying reactivity of ALS astrocytes using human stem cell models. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease affecting upper and lower motor neurons, characterised by muscle weakness rapidly leading to paralysis and death. Astrocytes respond to various insults by undergoing profound structural, molecular and functional changes called reactive astrogliosis. Reactive astrocytes are known to be implicated in ALS, although the mechanism controlling reactive transformation is unknown. So far, an astrocyte reactive state that favours an inflammatory phenotype has been reported in mouse models and human post-mortem tissue of ALS. In my thesis, I first demonstrate that hiPSCs-derived astrocytes undergo deleterious reactive transformation in response to tumor necrosis factor-alpha (TNF-α), interleukin 1α (IL-1α) and complement component1, subcomponent (C1q) but not to Lipopolysaccharides (LPS). I then characterised the reactive state in hiPSC-derived astrocytes from patients with VCP or SOD1 at a basal state and identified a distinct reactive profile of each mutation. The work in the thesis reveals that early reactive transformation can occur autonomously in human ALS astrocytes and with a striking degree of molecular and functional heterogeneity when comparing different disease-causing mutations. Looking into the mechanism underlying the diverse reactive states, the thesis shows decreased intron retention as a common alternative splicing mechanism in ALS astrocytes, associated with increased expression of transcripts regulating reactivity. This mechanism could potentially be targeted for therapeutic intervention. In parallel, recognizing the complex relationship between inflammation and ALS, this thesis examines how human astrocytes respond to extrinsic proinflammatory cues and ultimately how such responses might be perturbed or exacerbated in ALS. RNA binding proteins (RBPs) have been shown to play a key role in the pathogenesis of a variety of neurodegenerative disorders including ALS. Nuclear to cytoplasmic mislocalization and accumulation of RBPs has been identified as a pathological hallmark of the disease. This thesis combines the findings on RBP localisation with inflammatory responses, to explore how intrinsic mutation or/and extrinsic inflammation cues affect the localisation and ultimately the role of disease associated-RBPs in healthy and ALS astrocytes, to further our understanding of how pathogenic mechanisms may be interacting. Collectively, the work presented in this thesis shows the multiple layers of astrocytes reactive transformation in ALS.

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