Unique inflammatory transcriptional profiles distinguish between sALS cases of long and short disease duration

Abstract

Amyotrophic Lateral Sclerosis (ALS) is incurable, progressively fatal and a highly heterogeneous neuro- degenerative disease. Significant variation exists across the phenotypic presentation and genetic back- ground of the condition. The identification of TDP-43 protein aggregates as a pathological hallmark of ALS has established the condition as a proteinopathy. As TDP-43 is ubiquitously expressed and regulates transcription and splicing, understanding the transcriptional profiles associated with distinct ALS clinical phenotypes, particularly those associated with neuro-resilience, is a critical yet understudied area. We carried out transcriptional profiling on motor cortex samples from a cohort of sporadic ALS cases to determine the transcriptional signatures associated with long and short disease duration. Bioinformatic gene ontology analyses identified unique inflammatory transcriptional profiles associated with these extreme disease phenotypes. Our data demonstrate that inflammatory pathway dysregulation can dis- tinguish between phenotypic extremes in ALS. Characterising the molecular profile of clinically heteroge- neous cases provides vital insight in to the underlying pathophysiology of the condition. Understanding the molecular basis of factors which confer neuro-resilience will facilitate the development of targeted disease therapies. The ability to distinguish between molecular subtypes of ALS will enable the stratifica- tion of future trials to test these therapies and also to advance disease prognostication. 17e.elliott@ed.ac.uk