Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease

Abstract

We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive “multi-omic” analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.

CSF SerpinA1 in Creutzfeldt–Jakob disease and frontotemporal lobar degeneration

“…SerpinA1, also known as alpha‐1 antitrypsin, is an acute inflammatory protein belonging to the superfamily of serpins, which acts as a serine protease inhibitor. With the exception of liver and blood cells, its expression is strictly downregulated throughout the body, including the brain . Nonetheless, several pieces of evidence suggest that SerpinA1 may play a role in neurodegeneration.…”

“…Nonetheless, several pieces of evidence suggest that SerpinA1 may play a role in neurodegeneration. In this regard, overexpression of the protein or its RNA has been described in the brains of patients with Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD), suggesting that SerpinA1 overexpression may be detrimental to neuronal function . Moreover, the protein may play an anti‐inflammatory role by attenuating microglial activation, causing a reduction of neuroinflammation .…”

“…With the exception of liver and blood cells, its expression is strictly downregulated throughout the body, including the brain. 1 Nonetheless, several pieces of evidence suggest that Ser-pinA1 may play a role in neurodegeneration. In this regard, overexpression of the protein or its RNA has been ª 2020 The Authors.…”

“…This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. described in the brains of patients with Alzheimer's disease (AD) 2 and frontotemporal lobar degeneration (FTLD), 1 suggesting that SerpinA1 overexpression may be detrimental to neuronal function. 1 Moreover, the protein may play an anti-inflammatory role by attenuating microglial activation, causing a reduction of neuroinflammation.…”

“…described in the brains of patients with Alzheimer's disease (AD) 2 and frontotemporal lobar degeneration (FTLD), 1 suggesting that SerpinA1 overexpression may be detrimental to neuronal function. 1 Moreover, the protein may play an anti-inflammatory role by attenuating microglial activation, causing a reduction of neuroinflammation. [3][4][5] It is also known that the protein might diffuse out of venous blood and be released from the brain tissue into the cerebrospinal fluid (CSF).…”