Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Tam, Oliver H.; Rozhkov, Nikolay V.; Shaw, Regina; Kim, Duyang; Hubbard, Isabel; Fennessey, Samantha; Propp, Nadia; Fagegaltier, Delphine; Ostrow, Lyle W.; Phatnani, Hemali; Ravits, John; Dubnau, Josh; Hammell, Molly

doi:10.2139/ssrn.3364349

Cited by 12 publications

(23 citation statements)

References 32 publications

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“…An exacerbated innate immune response, with microglial activation as a predominant signature, has been recently shown in the ALS motor cortex (28). Furthermore, the only study which has investigated the whole transcriptome of the ALS motor cortex suggests that, among ALS cases, a subgroup of them is characterized by a higher inflammatory response (27). Our results also indicate that microglial-related neuroinflammatory changes in the human motor cortex are critical in the pathophysiology of this neurodegenerative disorder.…”

supporting

confidence: 68%

“…As the motor cortex is one of the major vulnerable and early affected regions in the disease, it represents a target region to disentangle key pathological processes in this neurodegenerative disorder. To date, few studies have performed a whole transcriptomic assessment of the CNS in ALS (25,26,27). However, this is the first deep transcriptome characterization of the ALS motor cortex with a multimodal approach that encompasses total RNAseq, cell-type deconvolution using human snRNAseq and immunohistochemical assessments.…”

Section: Discussionmentioning

confidence: 99%

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

Dols‐Icardo

Montal

Sirisi

et al. 2020

Preprint

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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.

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supporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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

Dols‐Icardo

Montal

Sirisi

et al. 2020

Preprint

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“…The resulting expression of the gypsy ERV contributes causally to the toxicity of glial expression of hTDP-43 because blocking gypsy expression was sufficient to extend lifespan of the animals expressing transgenic hTDP-43 in glia [32]. These data are parsimonious with the observation that HERV-K in particular [24,33] and RTEs/ERVs in general are expressed in post-mortem brain tissues from ALS patients [23,25,26]. HERV-K also is demonstrated to be neurotoxic in culture and leads to MND-like phenotypes in a rodent model [24].…”

Section: Introductionmentioning

confidence: 65%

“…TDP-43 pathology in animal models is now understood to cause global alterations in mRNA stability and splicing, biogenesis of some microRNAs (miRNAs), derepression of retrotransposons (RTEs) and endogenous retroviruses (ERVs), defects in nucleo-cytoplasmic transport, and activation of DNA damage response pathways [5,7,14,15,[19][20][21][22]. Most of these phenomena are observed not only in animal models but also in post-mortem tissues from human subjects [21,[23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

The Gypsy Endogenous Retrovirus Drives Non-Cell-Autonomous Propagation in a Drosophila TDP-43 Model of Neurodegeneration

Chang

Dubnau

2019

Current Biology

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“…Consortium sample processing has been, in part, previously described (52). In brief, RNA was extracted from flash-frozen post-mortem tissue using Trizol (ThermoFisher)-chloroform, followed by column purification (QIAGEN RNeasy minikit Figure 4A).…”

Section: Nygc Als Consortium Rna-seq Library Preparation From Bulk Timentioning

confidence: 99%

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

Prudencio¹,

Humphrey²,

Pickles³

et al. 2020

Journal of Clinical Investigation

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152

188

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No treatment for frontotemporal dementia (FTD), the second most common early-onset dementia, is available but therapeutics are being investigated to target the two main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hamstrung by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human iPSC-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease sub-types marked by TDP-43 inclusions. Lastly, we validated that truncated STMN2 RNA is elevated in the frontal cortex of a cohort of FTLD-TDP cases but not in controls or cases with progressive supranuclear palsy (PSP), a type of FTLD-tau. Further, in FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

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Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Cited by 12 publications

References 32 publications

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

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

The Gypsy Endogenous Retrovirus Drives Non-Cell-Autonomous Propagation in a Drosophila TDP-43 Model of Neurodegeneration

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

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