Chapters authored
Senataxin: A Putative RNA: DNA Helicase Mutated in ALS4—Emerging Mechanisms of Genome Stability in Motor Neurons
Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, autosomal dominant childhood- or adolescent-onset motor neuron disease caused by genetic defects in senataxin (SETX), a putative RNA–DNA helicase. Studies on the yeast SETX ortholog Sen1 revealed its role in small RNA termination pathways. It has been postulated that ALS4-associated neuronal pathologies could stem from defects in RNA metabolism and altered gene expression. Importantly, SETX prevents the accumulation of R-loops, which are potentially pathogenic RNA–DNA hybrids that stem from perturbations in transcription. SETX also interacts with the tumor suppressor BRCA1 that helps promote DNA double-strand break repair by homologous recombination. As such, SETX could contribute toward the removal of harmful R-loops and DSBs in postmitotic neurons. This chapter will visit the plausible mechanistic role of SETX in R-loop removal and DNA break repair that could prevent the activation of apoptotic cell death in neurons and pathological manifestation of ALS4.
Part of the book: Amyotrophic Lateral Sclerosis