Dataset Information

Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.

ABSTRACT: Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we provide evidence that CHMP7, a critical mediator of NPC quality control, is increased in nuclei of C9orf72 and sporadic ALS induced pluripotent stem cell (iPSC)-derived spinal neurons (iPSNs) and postmortem human motor cortex before the emergence of Nup alterations. Inhibiting the nuclear export of CHMP7 triggered Nup reduction and TDP-43 dysfunction and pathology in human neurons. Knockdown of CHMP7 alleviated disease-associated Nup alterations, deficits in Ran GTPase localization, defects in TDP-43-associated mRNA expression, and downstream glutamate-induced neuronal death. Thus, our data support a role for altered CHMP7-mediated Nup homeostasis as a prominent initiating pathological mechanism for familial and sporadic ALS and highlight the potential for CHMP7 as therapeutic target.

SUBMITTER: Coyne AN

PROVIDER: S-EPMC9022198 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.

Coyne Alyssa N AN Baskerville Victoria V Zaepfel Benjamin L BL Dickson Dennis W DW Rigo Frank F Bennett Frank F Lusk C Patrick CP Rothstein Jeffrey D JD

Science translational medicine 20210701 604

Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including <i>C9orf72</i> amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we ...[more]

PMID: 34321318

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Project description:The nuclear depletion and cytoplasmic aggregation of the RNA binding protein TDP-43 is widely considered a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and related neurodegenerative diseases. Recent studies have artificially reduced TDP-43 in wildtype human neurons to replicate loss of function associated events. Although this prior work has defined a number of gene expression and mRNA splicing changes that occur in a TDP-43 dependent manner, it is unclear how these alterations relate to authentic ALS where TDP-43 is not depleted from the cell but miscompartmentalized to variable extents. Here, in this population study, we generate ~30,000 qRT-PCR data points spanning 20 genes in induced pluripotent stem cell (iPSC) derived neurons (iPSNs) from >150 control, C9orf72 ALS/FTD, and sALS patients to examine molecular signatures of TDP-43 dysfunction. This data set defines a time dependent and variable profile of individual molecular hallmarks of TDP-43 loss of function within and amongst individual patient lines. Importantly, nearly identical changes are observed in postmortem CNS tissues obtained from a subset of patients whose iPSNs were examined. Notably, these studies provide evidence that induction of nuclear pore complex (NPC) injury via reduction of the transmembrane Nup POM121 in wildtype iPSNs is sufficient to phenocopy disease associated signatured of TDP-43 loss of function thereby directly linking NPC integrity to TDP-43 loss of function. Therapeutically, we demonstrate that the expression of all mRNA species associated with TDP-43 loss of function can be restored in sALS iPSNs via two independent methods to repair NPC injury. Collectively, this data 1) represents a substantial resource for the community to examine TDP-43 loss of function events in authentic sALS patient iPSNs, 2) demonstrates that patient derived iPSNs can accurately reflect actual TDP-43 associated alterations in patient brain, and 3) that targeting NPC injury events can be preclinically and reliably accomplished in an iPSN based platform of a sporadic disease.

Project description:Accumulation of hyperphosphorylated, ubiquitinated and N-terminally truncated TAR DNA-binding protein (TDP-43) is the pathological hallmark lesion in most familial and sporadic forms of FTLD-U and ALS, which can be subsumed as TDP-43 proteinopathies. In order to get more insight into the role of abnormal phosphorylation in the disease process, the identification of specific phosphorylation sites and the generation of phosphorylation-specific antibodies are mandatory. Here, we developed and characterized novel rat monoclonal antibodies (1D3 and 7A9) raised against phosphorylated S409/410 of TDP-43. These antibodies were used to study the presence of S409/410 phosphorylation by immunohistochemistry and biochemical analysis in a large series of 64 FTLD-U cases with or without motor neuron disease including familial cases with mutations in progranulin (n = 5), valosin-containing protein (n = 4) and linkage to chromosome 9p (n = 4), 18 ALS cases as well as other neurodegenerative diseases with concomitant TDP-43 pathology (n = 5). Our data demonstrate that phosphorylation of S409/410 of TDP-43 is a highly consistent feature in pathologic inclusions in the whole spectrum of sporadic and familial forms of TDP-43 proteinopathies. Physiological nuclear TDP-43 was not detectable with these mAbs by immunohistochemistry and by immunoblot analyses. While the accumulation of phosphorylated C-terminal fragments was a robust finding in the cortical brain regions of FTLD-U and ALS, usually being much more abundant than the phosphorylated full-length TDP-43 band, spinal cord samples revealed a predominance of full-length TDP-43 over C-terminal fragments. This argues for a distinct TDP-43 species composition in inclusions in cortical versus spinal cord cells. Overall, these mAbs are powerful tools for the highly specific detection of disease-associated abnormal TDP-43 species and will be extremely useful for the neuropathological routine diagnostics of TDP-43 proteinopathies and for the investigation of emerging cellular and animal models for TDP-43 proteinopathies.

Dataset Information

Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.

Publications

Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.

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