Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Abstract

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC; n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for βamyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and ADrelated genes despite the clinical and neuropathological distinctions between the two diseases.3

Epigenomics and transcriptomics analyses of multiple system atrophy brain tissue supports a role for inflammatory processes in disease pathogenesis

“…Overall, we consider that these recent studies by Bettencourt et al [1], Piras et al [4], and Rydbirk et al [5] are complementary, and bring important insights into the brain pathophysiology of MSA. All show changes in DNA methylation or in gene expression levels of genes that are more highly expressed in microglia/macrophages, therefore supporting previous studies highlighting the involvement of inflammatory processes in MSA (e.g.…”

“…Findings from Rydbirk et al [5] also report increased AREL1 and MHC class I HLA gene expression in MSA brains. We therefore investigated in our MSA cerebellar white matter RNAseq data [4] gene expression changes in all of the genes reported by Rydbirk et al [5]. Our study includes two independent cohorts of 66 MSA and 66 healthy controls and laser captured oligodendrocytes [4].…”

“…We therefore investigated in our MSA cerebellar white matter RNAseq data [4] gene expression changes in all of the genes reported by Rydbirk et al [5]. Our study includes two independent cohorts of 66 MSA and 66 healthy controls and laser captured oligodendrocytes [4]. Although we did not find differential expression for AREL1 or PHF3, we found a nominally significant (p < 0.05) downregulation of KTN1 (log2 FC = − 0.465), and upregulation of CTSZ (log2 FC = 0.817), NCS1 (log2 FC = 0.813) and ZIC4 (log2 FC = 1.520) in some groups of our cohort 1 (Supplementary Table S2).…”

SARS-CoV-2 Infectivity and Neurological Targets in the Brain

“…1 ) excised and each sector counted separately in 10 ml liquid scintillation fluid (Ultima Gold, PerkinElmer, Waltham, MA) in a Liquid Scintillation Counter (LS600016 LSC, Beckman, Fullerton, CA); relative signal intensities (Figs. 2 , 3 ) were expressed by comparing the ACE2 hybridization signal to the G3PDH signal for each polyA + mRNA on the MTE array (see Lukiw et al 1990 , 1992 ; Zhao et al 2001 ; Jaber et al 2017 ; Piras et al 2020 ). Statistical significance was analyzed using a two-way factorial analysis of variance ( p , ANOVA; SAS Institute, Cary, NC).…”

MOBP and HIP1 in multiple system atrophy: New α‐synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis

“…To gain insights into whether DNA methylation has a regulatory role on MOBP and HIP1 gene expression levels, we analysed data from 14 MSA cases and 10 healthy controls for which we had both DNA methylation 12 and gene expression data. 18 The genome-wide DNA methylation profiles used in this study were obtained as previously described. 12 Briefly, DNA methylation data were generated using the Infinium HumanMethylationEPIC BeadChip (Illumina), and analysed using R Bioconductor packages as previously described.…”