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

Aizawa, Hitoshi; Yamashita, Takenari; Kato, Haruhisa; Kimura, Takashi; Kwak, Shin

doi:10.3988/jcn.2019.15.1.62

Cited by 36 publications

(40 citation statements)

References 20 publications

(32 reference statements)

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“…Nevertheless, nuclear pore trafficking is important to some extent for normal TDP-43 localization. Perhaps unsurprisingly, in ALS, nuclear pore trafficking is disrupted, especially in cases of patients bearing mutations in TARDBP or C9ORF72 [223][224][225][226][227][228]. Aggregates of TDP-43 sequester nuclear pore proteins which would likely exacerbate TDP-43 mislocalization and accumulation into the protein aggregates [224].…”

Section: Potential Mechanisms Driving Tdp-43 Mislocalizationmentioning

confidence: 99%

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The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

228

170

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Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gainand loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclearto-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain-and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain-and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

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Section: Potential Mechanisms Driving Tdp-43 Mislocalizationmentioning

confidence: 99%

“…Furthermore, knockdown of nuclear import machinery (e.g. Importin-β) impair TDP-43 nuclear localization, increasing the cytoplasmic abundance of TDP-43 [ 223 ]. Mutagenesis of the NES does not alter TDP-43 localization suggesting the NES is non-functional, however manipulation of export machinery (e.g.…”

Section: Main Textmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

228

170

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“…These RBPs include the nuclear protein TAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) protein ( 149 , 156 , 157 ); for both proteins, a nuclear loss-of-function and a cytoplasmic gain-of-toxicity are discussed ( 149 ). Indications for NPC/NCT disruption in ALS are evident from nuclear membrane irregularities and abnormal NTR distribution in motor neurons ( 122 , 158 , 159 ) and in neurons with cytoplasmic TDP-43 inclusions in post-mortem ALS tissue ( 160 ).…”

Section: Nct Impairment As a General Concept In Neurodegeneration?mentioning

confidence: 99%

Nuclear Transport Deficits in Tau-Related Neurodegenerative Diseases

Diez

Wegmann

2020

Front. Neurol.

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Tau is a cytosolic microtubule binding protein that is highly abundant in the axons of the central nervous system. However, alternative functions of tau also in other cellular compartments are suggested, for example, in the nucleus, where interactions of tau with specific nuclear entities such as DNA, the nucleolus, and the nuclear envelope have been reported. We would like to review the current knowledge about tau-nucleus interactions and lay out possible neurotoxic mechanisms that are based on the (pathological) interactions of tau with the nucleus.

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“…FG nups comprise the NPC selectivity and permeability barrier through liquid-liquid phase separation of the FG repeat domains to form a hydrogel within the NPC central channel 86,103,104 and these are shown to exhibit neuropathological abnormalities in ALS tissue [105][106][107] . However, the specific relationship between FG nups and the expanded G4C2 allele in C9-ALS/FTLD is unknown.…”

Section: Nup62 Is a Modifier Of Expanded G4c2 Toxicity In Drosophilamentioning

confidence: 99%

Nup62 is recruited to pathological condensates and promotes TDP-43 insolubility in C9orf72 and sporadic ALS/FTLD.

Gleixner

Verdone

Otte

et al. 2021

Preprint

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Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) share clinical, neuropathological, and genetic features. This includes common genetic disease-causing mutations such as the expanded G4C2 repeat in the C9orf72 gene (C9-ALS/FTLD) and cytoplasmic and insoluble protein depositions of the TDP-43 in degenerating regions of the brain and spinal cord. Proposed mechanisms of toxicity in C9-ALS/FTLD are the production of repeat expansion transcripts and their dipeptide repeat proteins (DPRs) products which are hypothesized to drive nucleocytoplasmic transport defects. The nuclear pore complex (NPC) regulates nucleocytoplasmic trafficking by creating a selectivity and permeability barrier comprised of phenylalanine glycine nucleoporins (FG nups). However, the relationship between FG nups and TDP-43 pathology remains elusive. Here, we define two mechanisms through which TDP-43 promotes Nup62 nuclear depletion and cytoplasmic in C9-ALS/FTLD and sALS/FTLD. In C9-ALS/FTLD, poly-GR initiates the formation of TDP-43 containing stress granules (SGs) that trigger the nuclear loss and recruitment of Nup62 in vitro and in vivo. When colocalized, cytoplasmic TDP-43:Nup62 assemblies mature into insoluble inclusions through an interaction within the TDP-43 nuclear localization sequence (NLS) suggesting Nup62 promotes deleterious phase transitions. Absent of poly-GR, aberrant TDP-43 phase transitions in the cytoplasm recruits and mislocalizes Nup62 into pathological inclusions. The result of these cytoplasmic Nup62 and TDP-43 interactions are pathological and insoluble TDP-43:Nup62 assemblies that are observed in C9-ALS/FTLD and sALS/FTLD CNS tissue.

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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

Cited by 36 publications

References 20 publications

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Nuclear Transport Deficits in Tau-Related Neurodegenerative Diseases

Nup62 is recruited to pathological condensates and promotes TDP-43 insolubility in C9orf72 and sporadic ALS/FTLD.

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