2018 May 30 – Even though familial amyotrophic lateral sclerosis (ALS) accounts for 5 to 10% of all cases, the identification of genes implicated in rare familial forms of the pathology has significant impact on the unraveling of the molecular mechanisms underlying sporadic ALS. Emerging findings indicate that ALS-causing mutations affect key regulators of RNA processing, and dysregulated RNA processing occurring during development could eventually contribute to the increased vulnerability of mature motor neurons that characterizes ALS progression.
Of note, intron retention (IR) is the predominant RNA splicing change during early motor neurogenesis. A novel study shows that IR in the Splicing Factor Proline and Glutamine rich (SFPQ) transcript and nuclear loss of the SFPQ protein are common molecular hallmarks across diverse genetic and sporadic forms of ALS. Preliminary evidences were collected from RNA sequencing reads of spinal motor neurons differentiating in vitro and carrying a rare ALS-causing mutation in the gene VCP. Results were subsequently confirmed and generalised in two mouse transgenic models of ALS (SOD1G93A and VCPA232E) and upon examination of spinal cord post-mortem tissue from sporadic human ALS cases.
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