Loss of mouse Stmn2 function causes motor neuropathy

Juan, Irune Guerra San; Nash, Leslie A.; Smith, Kevin S.; Leyton-Jaimes, Marcel F.; Mei, Qian; Klim, Joseph R.; Limone, Francesco; Dorr, Alexander B; Couto, Alexander Benavides; Pintacuda, Greta; Joseph, Brian; Whisenant, D Eric; Noble, Caroline; Melnik, Veronika; Potter, Deirdre; Holmes, Amie L.; Verhage, Matthijs; Eggan, Kevin

doi:10.1016/j.neuron.2022.11.003

Cited by 7 publications

(5 citation statements)

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“…This view is further supported by the identification of key cryptic exon targets of TDP-43, such as UNC13A and STMN2 (refs. 9 , 11 – 14 , 25 – 27 ). However, because no method currently exists for the detection of TDP-43 dysfunction in living individuals, evidence that such loss of TDP-43 function occurs during early-stage disease rather than being an end-stage phenomenon remains elusive.…”

Section: Discussionmentioning

confidence: 99%

A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD

Irwin,

Jasin,

Braunstein

et al. 2024

Nat Med

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Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS–FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS–FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS–FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.

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Section: Discussionmentioning

confidence: 99%

A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD

Irwin,

Jasin,

Braunstein

et al. 2024

Nat Med

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“…Reduced Stmn2 expression has been implicated in human TDP-43 pathologies in ALS and AD, as well as in Parkinson’s disease patients and FTLD-tau patients 40,58–61 . Furthermore, the genetic loss of Stmn2 alone in mice results in motor neuropathy 62,63 . Additional dysregulation of transcripts, such as the upregulation of Meg3 and Apoe , as well as the downregulation of Fig4 , are seen in our model and mirror changes seen in neurodegenerative disease 64,65 .…”

Section: Discussionmentioning

confidence: 99%

“…It is difficult to establish whether the mutant NEMF R86S is pathologically interacting with Importin-β directly or is indirectly associating with Importin-β through aggregate-induced sequestration. However, the absence of nuclear import defects in an alone in mice results in motor neuropathy 62,63 . Additional dysregulation of transcripts, such as the upregulation of Meg3 and Apoe, as well as the downregulation of Fig4, are seen in our model and mirror changes seen in neurodegenerative disease 64,65 .…”

Section: Discussionmentioning

confidence: 99%

Importin-β specific nuclear transport defects recapitulate phenotypic and transcriptional alterations seen in neurodegeneration

Plessis-Belair,

Ravano,

Han

et al. 2024

Preprint

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Defects in Nucleocytoplasmic transport have been implicated as an important neurodegenerative pathway in ALS/FTD. Here, we show that a NemfR86S mutation results in the disruption of NCT both in vitro and in vivo. These disruptions are specific to Importin-β nuclear import, and result in the nuclear loss and cytoplasmic gain of NEMF, Importin-β, and TDP-43. We show that a transient nuclear import block is capable of inducing the mis-localization of TDP-43 and is associated with altered transcriptional expression of ALS, FTD, and AD/ARD genes. Taken together, these findings show that disrupted Importin-β nuclear import, whether through genetic forms such as Nemf mutations, or through pharmacological inhibition, is the primary driver of TDP-43 pathology, disease-related transcriptional alterations, and neurodegeneration.

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“…Lastly, it is important not to rule an indirect effect of TDP43 loss/truncation perhaps mediated via STMN2 or UNC13A, which were found to be reduced in the TDP43 truncation cases (Cooper-Knock et al, 2022). STMN2 knockout has recently been shown to lead to damaged mitochondria and microtubule alterations in cultured neurons (Krus et al, 2022;San Juan et al, 2022). Moreover, 18 F-2-fluoro-2-deoxy-D-glucose-PET imaging of UNC13A rs12608932 variant ALS cases showed hypometabolism is the brain, indicating a metabolic signature in these ALS cases (Calvo et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations

Allen,

Al Sultan,

Kabucho Kibirige

et al. 2023

Front. Aging Neurosci.

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A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.

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Loss of mouse Stmn2 function causes motor neuropathy

Cited by 7 publications

References 0 publications

A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD

A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD

Importin-β specific nuclear transport defects recapitulate phenotypic and transcriptional alterations seen in neurodegeneration

A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations

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