Dataset Information

Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy.

ABSTRACT:

Background

A G₄C₂ hexanucleotide repeat expansion in the noncoding region of C9orf72 is the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Putative disease mechanisms underlying c9FTD/ALS include toxicity from sense G₄C₂ and antisense G₂C₄ repeat-containing RNA, and from dipeptide repeat (DPR) proteins unconventionally translated from these RNA products.

Methods

Intracerebroventricular injections with adeno-associated virus (AAV) encoding 2 or 149 G₄C₂ repeats were performed on postnatal day 0, followed by assessment of behavioral and neuropathological phenotypes.

Results

Relative to control mice, gliosis and neurodegeneration accompanied by cognitive and motor deficits were observed in (G₄C₂)₁₄₉ mice by 6?months of age. Recapitulating key pathological hallmarks, we also demonstrate that sense and antisense RNA foci, inclusions of poly(GA), poly(GP), poly(GR), poly(PR), and poly(PA) DPR proteins, and inclusions of endogenous phosphorylated TDP-43 (pTDP-43) developed in (G₄C₂)₁₄₉ mice but not control (G₄C₂)₂ mice. Notably, proteins that play a role in the regulation of stress granules - RNA-protein assemblies that form in response to translational inhibition and that have been implicated in c9FTD/ALS pathogenesis - were mislocalized in (G₄C₂)₁₄₉ mice as early as 3?months of age. Specifically, we observed the abnormal deposition of stress granule components within inclusions immunopositive for poly(GR) and pTDP-43, as well as evidence of nucleocytoplasmic transport defects.

Conclusions

Our in vivo model of c9FTD/ALS is the first to robustly recapitulate hallmark features derived from both sense and antisense C9orf72 repeat-associated transcripts complete with neurodegeneration and behavioral impairments. More importantly, the early appearance of persistent pathological stress granules prior to significant pTDP-43 deposition implicates an aberrant stress granule response as a key disease mechanism driving TDP-43 proteinopathy in c9FTD/ALS.

SUBMITTER: Chew J

PROVIDER: S-EPMC6377782 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy.

Chew Jeannie J Cook Casey C Gendron Tania F TF Jansen-West Karen K Del Rosso Giulia G Daughrity Lillian M LM Castanedes-Casey Monica M Kurti Aishe A Stankowski Jeannette N JN Disney Matthew D MD Rothstein Jeffrey D JD Dickson Dennis W DW Fryer John D JD Zhang Yong-Jie YJ Petrucelli Leonard L

Molecular neurodegeneration 20190215 1

<h4>Background</h4>A G<sub>4</sub>C<sub>2</sub> hexanucleotide repeat expansion in the noncoding region of C9orf72 is the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Putative disease mechanisms underlying c9FTD/ALS include toxicity from sense G<sub>4</sub>C<sub>2</sub> and antisense G<sub>2</sub>C<sub>4</sub> repeat-containing RNA, and from dipeptide repeat (DPR) proteins unconventionally translated from these RNA products.<h4>Methods</h4>Intrace ...[more]

PMID: 30767771

Similar Datasets

Project description:GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contribution to the pathogenesis of neuronal injury. Moreover in motor neurons, which are the primary target of pathology in ALS, the presence of antisense foci (? (2), p < 0.00001) but not sense foci (? (2), p = 0.75) correlated with mislocalisation of TDP-43, which is the hallmark of ALS neurodegeneration. This has implications for translational approaches to C9ORF72 disease, and furthermore interacting RNA-processing factors and transcriptional activators responsible for antisense versus sense transcription might represent novel therapeutic targets.

Dataset Information

Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy.

Background

Methods

Results

Conclusions

Publications

Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy.

Similar Datasets

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