TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS

Zuo, Xinxin; Zhou, Jie; Li, Yin-Ming; Wu, Kai; Chen, Zonggui; Luo, Zhiwei; Zhang, Xiaorong; Liang, Yi; Esteban, Miguel A.; Zhou, Yu; Fu, Xiang‐Dong

doi:10.1038/s41594-020-00537-7

Cited by 111 publications

(95 citation statements)

References 79 publications

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“…Intriguingly, we find that proteins that aggregate after transient CPT-treatment are enriched for constituents of various disease-associated protein aggregates (Figure 4D). 68% (72/106) of them – or their mouse homologs – has already previously been identified in TDP-43 aggregates (Dammer et al 2012; Zuo et al 2021), Lewy bodies (McCormack et al 2019), or α -synuclein induced aggregates (Mahul-Mellier et al 2020), or found to aggregate in Huntington’s disease (Hosp et al 2017) or Alzheimer’s disease brains (Hales et al 2016; Kepchia et al 2020) (Figure 4 – figure supplement 1B).…”

Section: Resultsmentioning

confidence: 98%

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Huiting

et al. 2021

Preprint

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A loss of the checkpoint kinase ATM leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and a high risk to cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases result in a similar, widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including Huntingtin exon1 containing an expanded polyglutamine repeat, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a potent suppressor of it. Our findings reveal that various genotoxic conditions trigger widespread protein aggregation in a manner that is highly reminiscent of the aggregation occurring in situations of proteotoxic stress and in proteinopathies.

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Section: Resultsmentioning

confidence: 98%

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Huiting

et al. 2021

Preprint

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“…Notably a reduction in miR-1976 activity, motifs of which are detected in 76% of the C5 intronic regions, is expected to occur in some sporadic ALS patients due to a mutation ( rs17162257 ) in its enhancer (74) . Furthermore, several miRNAs, and their target genes, are recognized to be involved in the occurrence and pathophysiology of neurodegenerative diseases including ALS (75)(76)(77) . Thus, here we propose that a group of intronic sequences which accumulate in the cytoplasm of VCP mutant cells, as previously shown ( 23) , act as molecular sponges for miRNA, thus resulting in elevated expression of their target genes.…”

Section: Discussionmentioning

confidence: 99%

Diminished miRNA activity is associated with aberrant cytoplasmic intron retention in ALS pathogenesis

Petric-Howe

Crerar

Neeves

et al. 2021

Preprint

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SUMMARYIntron retention (IR) is now recognized as a dominant splicing event during motor neuron (MN) development, however the role and regulation of intron-retaining transcripts (IRTs) localized to the cytoplasm remain particularly understudied. By resolving the spatiotemporal dynamics of IR underlying distinct stages of MN lineage restriction, we identify a cytoplasmic group of IRTs that is not associated with reduced expression of their own genes but instead with an upregulation of predicted target genes of specific miRNAs, the motifs of which are enriched within the intronic sequences of this group. Next, we show that ALS-causing VCP mutations lead to a selective increase in IR of this particular class of introns. This in turn temporally coincides with an increase in the expression level of predicted target genes of these miRNAs, providing a potential mechanistic insight into ALS pathogenesis. Altogether, we propose a novel role for the cytoplasmic intronic sequences in regulating miRNA activity through miRNA sequestration, which potentially contributes to ALS pathogenesis.

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“…Mitochondrial dysfunction has been implicated in the disease progression since the observation of abnormal mitochondrial morphology and the identification of SOD1 mutations in ALS patients [ 136 ]. SOD1 is involved in the breakdown of reactive oxygen species (ROS) within the cell [ 146 ]. Reactive oxygen species are a byproduct of the mitochondrial electron transport chain.…”

Section: Pathogenic Mechanisms Of Tdp-43 In Cell and Animal Modelsmentioning

confidence: 99%

“…Reactive oxygen species are a byproduct of the mitochondrial electron transport chain. Therefore, ALS was linked with dysfunctional mitochondria through oxidative stress [ 146 ]. ALS patient tissues display abnormal mitochondrial morphology [ 147 ].…”

Section: Pathogenic Mechanisms Of Tdp-43 In Cell and Animal Modelsmentioning

confidence: 99%

“…TDP-43 links mitochondrial dysfunction to ALS and FTLD through its regulation of nuclear-encoded mitochondrial genes [ 143 ]. Mitochondrial caspases cleave TDP-43 into the pathological 25 and 35 kDa fragments associated with ALS and FTLD, thereby linking mitochondrial defects and TDP-43 to disease proteinopathy [ 146 ].…”

Section: Pathogenic Mechanisms Of Tdp-43 In Cell and Animal Modelsmentioning

confidence: 99%

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Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD

Wood

Gurfinkel

Polain

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.

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TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS

Cited by 111 publications

References 79 publications

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Diminished miRNA activity is associated with aberrant cytoplasmic intron retention in ALS pathogenesis

Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD

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