Kremers, Charlotte Johanna Pauline; (2022) Characterising a novel mouse model of Amyotrophic Lateral Sclerosis: a study of senataxin pathology in ALS4. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is characterised by degeneration of motor neurons, leading to progressive muscle weakness, muscle atrophy and premature death. Approximately 10% of ALS cases are familial, resulting from mutations in several genes, including the RNA-binding proteins FUS, TDP-43 and senataxin. Multiple complex cellular mechanisms have been proposed to play a role in motor neuron pathology in ALS, including RNA dysregulation, DNA damage, mitochondrial dysfunction and axonal transport deficits. Autosomal dominant mutations in senataxin cause ALS4, a non-fatal, slowly progressing form of ALS with juvenile onset. Senataxin is a DNA/RNA helicase that is involved in transcription termination, RNA processing and splicing. Unlike other forms of ALS, the cellular pathways contributing to motor neuron degeneration in ALS4 remain largely under-investigated. The experiments described in this Thesis aimed to improve the understanding of the pathological mechanisms underlying ALS4 disease by using a novel transgenic mouse model expressing the R2136H mutation in human senataxin (SETX). The SETX-R2136H mouse model was first characterised by longitudinal behavioural testing of motor function and in vivo muscle force electrophysiology. Inverted grid and physiology analysis revealed a motor phenotype and deficit in muscle strength in mutant SETX-R2136H mice at 6 months of age. Potential molecular pathomechanisms underlying disease were next investigated. Spinal cords of SETX-R2136H mice as well as SETX- R2136H cultured embryonic primary motor neurons exhibited evidence of increased DNA damage. Although the mitochondrial membrane potential was unchanged in SETX-R2136H cultured primary motor neurons, the expression of a mitochondrial biogenesis gene and protein levels of two oxidative phosphorylation complexes were significantly reduced in SETX-R2136H cultured primary motor neurons and spinal cord, respectively. Furthermore, both in vivo and in vitro SETX-R2136H motor neurons displayed reduced maximum retrograde axonal transport speeds. SETX-R2136H cultured primary motor neurons also showed an enhanced vulnerability to apoptotic activation and an increased tendency to form stress granules. Collectively, these findings demonstrate that mutant SETX-R2136H mice develop an ALS4-like phenotype and suggest that several molecular pathomechanisms are likely to play a key role in ALS4 pathology.

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