Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

Abstract

400w)Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. A major neuropathological finding in ALS is the coexistence of glial activation and aggregation of the phosphorylated transactive response DNA-binding protein 43-kDa (pTDP43) in the motor cortex at the earliest stages of the disease. Despite this, the transcriptional alterations associated with these pathological changes in this major vulnerable brain region have yet to be fully characterized. Here, we have performed massive RNA sequencing of the motor cortex of ALS (n=11) and healthy controls (HC; n=8). We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synapse related pathways.The assembly of gene co-expression modules confirmed the involvement of these two principal transcriptomic changes, and showed a strong negative correlation between them.Furthermore, cell-type deconvolution using human single-nucleus RNA sequencing data as reference demonstrated that microglial cells are overrepresented in ALS compared to HC. Importantly, we also show for the first time in the human ALS motor cortex, that microgliosis is mostly driven by the increased proportion of a microglial subpopulation characterized by gene markers overlapping with the recently described disease associated microglia (DAM).Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that variability in pTDP43 aggregation among patients negatively correlates with the proportion of microglial cells. In conclusion, we report that neuroinflammatory changes in ALS motor cortex are dominated by microglia which is concomitant with a reduced expression of postsynaptic transcripts, in which DAM might have a prominent role. Microgliosis therefore represents a promising avenue for therapeutic intervention in ALS.

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

“…An extensive body of evidence has suggested that glia contribute to the neurodegeneration observed in ALS and FTD (9,10,(110)(111)(112)(113). Transcriptional assessments and proteomic approaches across the ALS/FTD spectrum have reported robust glia signatures and glia protein modules, respectively, emphasizing a glia involvement in inflammation and contribution to disease (109,(113)(114)(115).…”

The Big Picture of Neurodegeneration: A Meta Study to Extract the Essential Evidence on Neurodegenerative Diseases in a Network-Based Approach

“…Among the non-control patients, 84% were classified as having a moderate or severe condition in the transcriptome experiments and 90% in the proteome experiments. In total, transcriptomic data of 39 studies (Blalock et al, 2004 , 2011 ; Zhang et al, 2005 ; Dunckley et al, 2006 ; Lesnick et al, 2007 ; Liang et al, 2007 ; Scherzer et al, 2007 ; Simunovic et al, 2009 ; Cox et al, 2010 ; Elstner et al, 2011 ; Dumitriu et al, 2012 , 2016 ; Feyeux et al, 2012 ; Berchtold et al, 2013 ; Hokama et al, 2014 ; Riley et al, 2014 ; Calligaris et al, 2015 ; Dijkstra et al, 2015 ; Labadorf et al, 2015 ; Magistri et al, 2015 ; Prudencio et al, 2015 ; Raman et al, 2015 ; Ring et al, 2015 ; Kapeli et al, 2016 ; Lin et al, 2016 ; Scheckel et al, 2016 ; Lim et al, 2017a , b ; Gagliardi et al, 2018 ; Mehta et al, 2018 ; Stopa et al, 2018 ; Mathys et al, 2019 ; Meyer et al, 2019 ; Otake et al, 2019 ; Swindell et al, 2019 ; Switońska et al, 2019 ; Al-Dalahmah et al, 2020 ; Dols-Icardo et al, 2020 ; Higginbotham et al, 2020 ) and proteomic data of 22 studies were acquired (Fang et al, 2009 ; van Dijk et al, 2012 ; Varghese et al, 2013 ; McQuade et al, 2014 ; Riley et al, 2014 ; Collins et al, 2015 ; Dumitriu et al, 2016 ; Hondius et al, 2016 ; Ratovitski et al, 2016 ; Lachén-Montes et al, 2017 , 2019 ; Seyfried et al, 2017 ; Umoh et al, 2018 ; Zhang et al, 2018 …”