Large-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival

Abstract

Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in ALS. Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Mutations in the tail and rod domains of the neurofilament heavy‐chain gene increase the risk of ALS

“…A recent study reported a noncoding repeat polymorphism in the same domain as being protective against ALS 30 , suggesting an intricate genetic architecture in this domain with different classes of variants playing different roles. In recent years, several studies have shown that noncoding variants have a major role in ALS: for example, enhancer variants in CAV1 and CAV2 31,32 and intronic variants in UNC13A 33,34 . Our findings expand this by also implicating NEFH noncoding variants in ALS.…”