Mitochondrial bioenergetic dysfunction and cryptic splicing of stathmin-2 are neuropathological markers of disease duration in sporadic amyotrophic lateral sclerosis

A striking feature of sporadic amyotrophic lateral sclerosis (ALS) is the marked heterogeneity in disease duration; despite the stark median survival of three years from symptom onset, 10-20% of people with ALS survive longer than 10 years. An improved understanding of the mechanisms underpinning this is vital to revealing the biological basis of disease resilience. Accumulating experimental and pathological evidence implicates mitochondrial bioenergetic dysfunction and TDP-43 nuclear loss-of-function in the aetiopathogenesis of ALS. However, the relevance of these two molecular dysfunctions to disease duration and resilience in ALS is unknown. We curated a cohort of sporadic ALS cases comprising clinically linked autopsy samples to identify molecular neuropathological correlates of disease duration. We developed a novel dual BaseScope RNA in situ hybridisation probe that labels mitochondrial complex 1 transcript (MT-ND2) and truncated stathmin-2 (STMN2) transcripts to measure mitochondrial bioenergetic function and TDP-43 loss-of-function, respectively, in ventral horn neurons. We first show that there is dysfunctional mitochondrial bioenergetics in sporadic ALS. We observed reduced expression of MT-ND2 and increased expression of truncated STMN2 in ALS cases (N=20) compared to sex- and age-matched controls (N=10). We show that these findings correlate with ALS disease duration. Further mechanistic studies are needed to explore whether manipulation of STMN2 expression, by either suppressing cryptic splicing or overexpression, could modify disease duration.