Connecting TDP-43 Pathology with Neuropathy

Klim, Joseph R.; Pintacuda, Greta; Nash, Leslie A.; Juan, Irune Guerra San; Eggan, Kevin

doi:10.1016/j.tins.2021.02.008

Cited by 48 publications

(57 citation statements)

References 131 publications

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“…The NTD plays a crucial role in determining the type of TDP-43 species present in the cell: monomers, dimers or oligomers. The dimeric and oligomeric forms of TDP-43 are thought to be both functionally active The disease-causing mutations inserting or deleting a phosphorylation residue with a well-known effect are underlined in red and the disease-causing mutations inserting a cysteine residue are underlined in green (Pesiridis et al, 2009;Millecamps et al, 2010;Solski et al, 2012;Van Blitterswijk et al, 2012;Chen et al, 2019Chen et al, , 2021Agrawal et al, 2021;Klim et al, 2021;Tziortzouda et al, 2021).…”

Section: Structure Of Tdp-43mentioning

confidence: 99%

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions

et al. 2022

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TAR DNA-binding protein 43, mostly referred to as TDP-43 (encoded by the TARDBP gene) is strongly linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). From the identification of TDP-43 positive aggregates in the brains and spinal cords of ALS/FTD patients, to a genetic link between TARBDP mutations and the development of TDP-43 pathology in ALS, there is strong evidence indicating that TDP-43 plays a pivotal role in the process of neuronal degeneration. What this role is, however, remains to be determined with evidence ranging from gain of toxic properties through the formation of cytotoxic aggregates, to an inability to perform its normal functions due to nuclear depletion. To add to an already complex subject, recent studies highlight a role for TDP-43 in muscle physiology and disease. We here review the biophysical, biochemical, cellular and tissue-specific properties of TDP-43 in the context of neurodegeneration and have a look at the nascent stream of evidence that positions TDP-43 in a myogenic context. By integrating the neurogenic and myogenic pathological roles of TDP-43 we provide a more comprehensive and encompassing view of the role and mechanisms associated with TDP-43 across the various cell types of the motor system, all the way from brain to limbs.

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Section: Structure Of Tdp-43mentioning

confidence: 99%

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions

et al. 2022

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“…For example, it has been shown that TDP-43 normally suppresses a cryptic polyadenylation site within the axonal protein STMN2; loss of nuclear TDP-43 leads to NMD of the STMN2 mRNA and near-total knock-down of the protein ( 63 , 64 ). LoF of STMN2 has been associated with motor neuron toxicity ( 65 ), genetic variants within STMN2 have been associated with ALS severity ( 66 ) and the interaction between TDP-43 and STMN2 mRNA is the focus of active translational research.…”

Section: Als Risk Genes Converge In Pathwaysmentioning

confidence: 99%

Advances in the genetic classification of amyotrophic lateral sclerosis

Cooper‐Knock

Harvey

Zhang

et al. 2021

Current Opinion in Neurology

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Purpose of review Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease where disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture which will be necessary for comprehensive disease subclassification. Recent findings We summarise recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach including clinicians, geneticists and pathologists. Summary The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant but the potential reward for successful disease subclassification is large-scale and effective personalized medicine.

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“…This hnRNP family protein is predominantly localized in the nucleus but also shuttles to the cytoplasm, thus it may regulate various steps of RNA biogenesis during muscle development and in neuromuscular disease ( Picchiarelli and Dupuis, 2020 ). Mutations in TARDBP lead to familial ALS and frontotemporal dementia (FTD), indirectly affecting muscle function ( Klim et al, 2021 ). In zebrafish, knockout of tardbp causes muscle degeneration, suggesting that it may be involved in muscle maintenance ( Schmid et al, 2013 ), but the post-transcriptional mechanism remains unclear.…”

Section: Rna-binding Proteins Involved In Skeletal Muscle Development Regeneration and Diseasementioning

confidence: 99%

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Shi

Grifone

2021

Front. Cell Dev. Biol.

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Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations.

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Connecting TDP-43 Pathology with Neuropathy

Cited by 48 publications

References 131 publications

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions

Advances in the genetic classification of amyotrophic lateral sclerosis

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

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