Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Yamashita, Takenari; Aizawa, Hitoshi; Teramoto, Sayaka; Akamatsu, Megumi; Kwak, Shin

doi:10.1038/srep39994

Cited by 31 publications

(31 citation statements)

References 48 publications

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“…5i, j ). These data suggest that the defects in the nucleocytoplasmic transport pathway are consistently observed in cortical neurons with ectopic expression of aggregated or mutant TDP-43, in fibroblasts and iPSC-derived neurons from ALS cases, as well as in a mechanistic ALS mouse model 26 . The dysregulation of nucleocytoplasmic shuttling and disruption of the NM and NPCs may be a common mechanism in both sALS and fALS exhibiting TDP-43 proteinopathy.…”

Section: Resultsmentioning

confidence: 66%

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

et al. 2018

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The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here, we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates, and found them enriched for components of the nuclear pore complex (NPC) and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins (Nups) and transport factors (TFs), and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts, and iPSC-derived neurons. Nuclear pore pathology is present in brain tissue from sporadic ALS cases (sALS) and those with genetic mutations in TARDBP (TDP-ALS) and C9orf72 (C9-ALS). Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

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Section: Resultsmentioning

confidence: 66%

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

et al. 2018

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“…The downstream calcium-dependent proteolytic enzymes known as calpains would then be activated (Adamec et al, 1998;Andres et al, 2013) and ultimately cleave substrates of receptors, enzymes or cytoskeletal proteins (Chan and Mattson, 1999), and possibly Nup358. In support of this notion, previous reports have shown that in diverse excitotoxic events, nucleoporins such as Nup153, Nup62, Nup88 and Nup358 were cleaved by activated calpains (Bano et al, 2010;Sugiyama et al, 2017;Yamashita et al, 2017). Moreover, under conditions of an increased calcium concentration, calpains contribute to the proteolysis of such AIS proteins as AnkG (Leterrier et al, 2015).…”

Section: Kcl Treatment Decreases Nup358 Expressionmentioning

confidence: 60%

Ankyrin-G induces nucleoporin Nup358 to associate with the axon initial segment of neurons

Khalaf

Roncador

Pischedda

et al. 2019

Journal of Cell Science

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Nup358 (also known as RanBP2) is a member of the large nucleoporin family that constitutes the nuclear pore complex. Depending on the cell type and the physiological state, Nup358 interacts with specific partner proteins and influences distinct mechanisms independent of its role in nucleocytoplasmic transport. Here, we provide evidence that Nup358 associates selectively with the axon initial segment (AIS) of mature neurons, mediated by the AIS scaffold protein ankyrin-G (AnkG, also known as Ank3). The N-terminus of Nup358 is demonstrated to be sufficient for its localization at the AIS. Further, we show that Nup358 is expressed as two isoforms, one full-length and another shorter form of Nup358. These isoforms differ in their subcellular distribution in neurons and expression level during neuronal development. Overall, the present study highlights an unprecedented localization of Nup358 within the AIS and suggests its involvement in neuronal function. This article has an associated First Person interview with the first author of the paper.

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Section: Introductionmentioning

confidence: 77%

“…This study found that disruption of the NPC was correlated with TDP-43 mislocalization in the spinal motor neurons of patients with sALS. TDP-43 pathology occurs in motor neurons that demonstrate abnormal activation of calpains, and so we suspect that disruption of the NPC in sALS is related to calpain activation 10. NUP62 immunoreactivity was observed along the round-shaped nuclear membrane in normal motor neurons (Fig.…”

Section: Discussionmentioning

confidence: 93%

“…Disruption of nucleoporins has been reported in an sALS mouse model (ADAR2 flox/flox /VAChT-Cre or AR2 mice),9 in which the adenosine deaminase acting on RNA 2 (ADAR2) was conditionally knocked out 10. Analogous changes in nucleoporins have also been observed in preliminary studies of the ADAR2-deficient motor neurons of sALS patients 10. ADAR2 regulates Ca 2+ influx through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors via adenosine-to-inosine conversion at the glutamine/arginine site of GluA2 mRNA, which makes ADAR2 is a key factor in acquired Ca 2+ resistance in motor neurons.…”

Section: Introductionmentioning

confidence: 99%

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Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein

et al. 2019

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Background and PurposeDisruption of nucleoporins has been reported in the motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS). However, the precise changes in the morphology of nucleoporins associated with the pathology of the 43-kDa TAR DNA-binding protein (TDP-43) in the disease process remain unknown. We investigated the expression of nucleoporins that constitute the nuclear pore complex (NPC) in spinal motor neurons that exhibit sALS in relation to TDP-43 pathology, which is a reliable neuropathological hallmark of sALS.MethodsParaffin-embedded sections of the lumbar spinal cord were obtained for immunofluorescence analysis from seven control subjects and six sALS patients. Anti-TDP-43 antibody, anti-nucleoporin p62 (NUP62) antibody, and anti-karyopherin beta 1 (KPNB1) antibody were applied as primary antibodies, and then visualized using appropriate secondary antibodies. The sections were then examined under a fluorescence microscope.ResultsNUP62 and KPNB1 immunoreactivity appeared as a smooth round rim bordering the nuclear margin in normal spinal motor neurons that exhibited nuclear TDP-43 immunoreactivity. sALS spinal motor neurons with apparent TDP-43 mislocalization demonstrated irregular, disrupted nuclear staining for NUP62 or KPNB1. Some atrophic sALS spinal motor neurons with TDP-43 mislocalization presented no NUP62 immunoreactivity.ConclusionsOur findings suggest a close relationship between NPC alterations and TDP-43 pathology in the degenerative process of the motor neurons of sALS patients.

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Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Cited by 31 publications

References 48 publications

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

Ankyrin-G induces nucleoporin Nup358 to associate with the axon initial segment of neurons

Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein

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