Salomonsson, Sally Evita; (2022) Investigation of repeat-associated non-AUG translation and dipeptide repeat proteins in C9orf72-associated ALS/FTD. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A hexanucleotide repeat expansion in the gene C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion causes intranuclear RNA foci and repeat-associated non-AUG (RAN) translation of five aberrant dipeptide repeat proteins (DPRs). Both RNA foci and DPRs are widely distributed in the patient brain, alongside reduced expression of the C9orf72 protein, involved in proteostasis, vesicle trafficking and immunity. TDP-43 neuropathology arises in nearly all cases and correlates with clinical symptoms and neurodegeneration. The primary cause of C9orf72-associated ALS/FTD is unknown, as the putative pathomechanisms may synergise to exert neurotoxicity. Evidence supports a pathogenic role of DPRs, although endogenous neuronal RAN translation of DPRs is not well understood. Moreover, the effects of the mutation on selectively vulnerable motor neurons are incompletely understood, e.g. in terms of functional connectivity development and synaptic integrity. Consequently, the overarching aims of this thesis are to uncover mechanisms regulating endogenous neuronal DPR levels and to identify mutation-related and DPR-specific changes to motor neuron phenotypes to ultimately aid discovery of therapeutic targets, as currently no effective therapeutics exist. First, a C9orf72 ALS/FTD patient-derived iPSC-motor neuron model was generated to investigate early molecular and functional phenotypes and endogenous RAN translation modifiers, which revealed network hyposynchrony and a novel pathway involved in RAN translation. Next, neuromuscular junction integrity was assessed in the context of selective DPR expression, in novel C9orf72 ALS/FTD knock-in mouse models with temporally and spatially relevant expression of DPRs driven by the mouse C9orf72 promoter and concomitant C9orf72 haploinsufficiency, which led to discovery of presynaptic structural abnormalities at neuromuscular junctions. This work contributes new insights into the pathomechanisms of C9orf72 ALS/FTD within the motor system and new directions in the search for therapeutic targets, with potential relevance for other neurodegenerative diseases and polynucleotide repeat disorders.

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