TDP-43 maximizes nerve conduction velocity by repressing a cryptic exon for paranodal junction assembly in Schwann cells

Chang, Kae-Jiun; Agrawal, Ira; Vainshtein, Anna; Ho, Wan Yun; Xin, Wendy; Tucker‐Kellogg, Greg; Susuki, Keiichiro; Peles, Elior; Ling, Shuo-Chien; Chan, Jonah R.

doi:10.7554/elife.64456

Cited by 14 publications

(17 citation statements)

References 75 publications

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“…Aggregation of TARDBP in amyotrophic lateral sclerosis (ALS) could lead to the loss of MBP with compensatory response of oligodendrocytes, which indirectly might serve as an additional evidence for the involvement of TARDBP in the transport of MBP granules [ 52 , 53 ]. The TARDBP was shown to have a functional role in axon–glial interactions in the PNS, and loss of its function in Schwann cells led to impaired conduction velocity and motor behavior [ 54 ]. In the MBP bound complex we also identified the RNA-editing enzyme ADAR1 (RNA-specific adenosine deaminase [ 55 ]).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Atlas of the Myelin Basic Protein Interaction Landscape

et al. 2021

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Intrinsically disordered myelin basic protein (MBP) is one of the key autoantigens in autoimmune neurodegeneration and multiple sclerosis particularly. MBP is highly positively charged and lacks distinct structure in solution and therefore its intracellular partners are still mostly enigmatic. Here we used combination of formaldehyde-induced cross-linking followed by immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate the interaction network of MBP in mammalian cells and provide the list of potential MBP interacting proteins. Our data suggest that the largest group of MBP-interacting proteins belongs to cellular proteins involved in the protein translation machinery, as well as in the spatial and temporal regulation of translation. MBP interacts with core ribosomal proteins, RNA helicase Ddx28 and RNA-binding proteins STAU1, TDP-43, ADAR-1 and hnRNP A0, which are involved in various stages of RNA biogenesis and processing, including specific maintaining MBP-coding mRNA. Among MBP partners we identified CTNND1, which has previously been shown to be necessary for myelinating Schwann cells for cell-cell interactions and the formation of a normal myelin sheath. MBP binds proteins MAGEB2/D2 associated with neurotrophin receptor p75NTR, involved in pathways that promote neuronal survival and neuronal death. Finally, we observed that MBP interacts with RNF40–a component of heterotetrameric Rnf40/Rnf20 E3 ligase complex, recruited by Egr2, which is the central transcriptional regulator of peripheral myelination. Concluding, our data suggest that MBP may be more actively involved in myelination not only as a main building block but also as a self-regulating element.

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Section: Resultsmentioning

confidence: 99%

Comprehensive Atlas of the Myelin Basic Protein Interaction Landscape

et al. 2021

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“…In the case of the Neurofascin gene, TDP-43 binding to its mRNA is important for its expression. In TDP-43 loss of function phenotype, a previously unidentified cryptic exon is retained in the neurofascin gene targeting the mRNA to undergo nonsense-mediated decay (Chang et al, 2021 ). TDP-43 regulates the expression of stathmin-2, a neuronal growth associated factor.…”

Section: Common Mechanisms Of Neurodegeneration In Als and Ftdmentioning

confidence: 99%

DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication

Wang

Manohar

Britz

et al. 2021

Front. Mol. Neurosci.

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Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration.

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“…This is consistent with a recent rodent study that found no effect of selective TDP-43 deletion in oligodendrocytes on paranodal assembly. 38 Further studies are needed to ascertain myelination status and the influence of TARDBP mutation over time to model prolonged disease.…”

Section: Discussionmentioning

confidence: 99%

TDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

Barton

Magnani

James

et al. 2021

Brain Communications

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Oligodendrocytes are implicated in Amytrophic Lateral Sclerosis pathogenesis and display TDP-43 pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from patient-derived induced pluripotent stem cell lines harbouring mutations in the TARDBP gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment via whole-cell patch clamping, and three-dimensional cultures, no differences in oligodendrocyte differentiation, maturation or myelination were identified. Further, expression analysis for monocarboxylate transporter 1 (a lactate transporter) coupled with a glycolytic stress test showed no deficit in lactate export. However, using confocal microscopy, we report TDP-43 mutation dependent pathological mis-accumulation of TDP-43. Furthermore, using in vitro patch-clamp recordings, we identified functional Ca2+-permeable AMPA receptor dysregulation in oligodendrocytes. Together, these findings establish a platform for further interrogation of the role of oligodendrocytes and cellular autonomy in TDP-43 proteinopathy.

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TDP-43 maximizes nerve conduction velocity by repressing a cryptic exon for paranodal junction assembly in Schwann cells

Cited by 14 publications

References 75 publications

Comprehensive Atlas of the Myelin Basic Protein Interaction Landscape

Comprehensive Atlas of the Myelin Basic Protein Interaction Landscape

DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication

TDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

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