Analysis of RNA stability in ALS patients

Abstract

Studies of the pathological features of Amyotrophic Lateral Sclerosis (ALS) implicate anomalous RNA misprocessing with the disease. Here, we investigate motor cortex RNA stability and its genetic underpinning in a cohort of ALS patients. RNA stability captures information about RNA misprocessing and is estimated using total RNA sequencing data. Analyses of RNA stability estimates show that outliers occur disproportionally in neuronal pathways relevant to ALS such as synaptic vesicle recycling and neuron projection regeneration. The genetics underlying RNA stability are studied firstly by relating the most common mutation underlying ALS, C9orf72 expansions, to RNA stability. We find that C9orf72 positive samples generally have lower RNA stabilities. Next, evolutionary scores as well as scores for impact on RNA-binding affinity are calculated for genetic variants. However, relating these scores with RNA stabilities did not yield any significant results. Overall, we demonstrate the importance of using RNA stability for studying ALS and recommend several improvements to the methodology, including the incorporation of micro-RNAs and transcript features into the statistical models, to capitalize on its potential for further discoveries in ALS and other phenotypes.