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TAR DNA-binding protein 43 (TARDBP) is a crucial component in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder. TARDBP encodes the transactive response DNA-binding protein 43 (TDP-43), which is frequently found in pathological inclusions in various forms of ALS [1]. Mutations in TARDBP have been identified in both familial and sporadic ALS cases, highlighting its significance in the disease [2][3][4]. TDP-43 is a 43 kDa nuclear protein involved in RNA metabolism [5]. It is the major protein found in the ubiquitinated inclusions in affected motor neurons in ALS cases [6]. Studies have shown that TARDBP mutations are prevalent in Italian ALS patients, further emphasizing its role in the disease [7].
TDP-43 is an RNA/DNA-binding protein that belongs to the heterogeneous nuclear ribonucleoprotein family [8]. It has been associated with various cellular functions, including transcriptional regulation and splicing [9]. The protein is essential for early embryonic development and is highly conserved across different species [10]. In ALS, TDP-43 forms aggregates in the motor cortex of aging brains, indicating its involvement in the disease progression [11].
The complexity of ALS pathophysiology involves interactions with other proteins and pathways. For instance, TDP-43 interacts with progranulin to reverse motor neuron defects, highlighting its neurotrophic effects [12]. Additionally, loss of TDP-43 in zebrafish models leads to muscle degeneration and reduced motor neuron axon outgrowth, further underlining its role in ALS-related degeneration [13].
References:
[1] V. Soldatov, M. Kukharsky, А. Белых, A. Sobolev, & A. Deykin, "Retinal damage in amyotrophic lateral sclerosis: underlying mechanisms", Eye and Brain, vol. Volume 13, p. 131-146, 2021. https://doi.org/10.2147/eb.s299423
[2] J. Sreedharan, I. Blair, V. Tripathi, X. Hu, C. Vance, B. Rogeljet al., "Tdp-43 mutations in familial and sporadic amyotrophic lateral sclerosis", Science, vol. 319, no. 5870, p. 1668-1672, 2008. https://doi.org/10.1126/science.1154584
[3] D. Bosco, N. Lemay, H. Ko, H. Zhou, C. Burke, T. Kwiatkowskiet al., "Mutant fus proteins that cause amyotrophic lateral sclerosis incorporate into stress granules", Human Molecular Genetics, vol. 19, no. 21, p. 4160-4175, 2010. https://doi.org/10.1093/hmg/ddq335
[4] S. Lattante, G. Rouleau, & E. Kabashi, "tardbpandfusmutations associated with amyotrophic lateral sclerosis: summary and update", Human Mutation, vol. 34, no. 6, p. 812-826, 2013. https://doi.org/10.1002/humu.22319
[5] S. Dzieciolowska, P. Drapeau, & G. Armstrong, "Augmented quantal release of acetylcholine at the vertebrate neuromuscular junction following tdp-43 depletion", Plos One, vol. 12, no. 5, p. e0177005, 2017. https://doi.org/10.1371/journal.pone.0177005
[6] P. Bose, G. Armstrong, & P. Drapeau, "Neuromuscular junction abnormalities in a zebrafish loss-of-function model of tdp-43", Journal of Neurophysiology, vol. 121, no. 1, p. 285-297, 2019. https://doi.org/10.1152/jn.00265.2018
[7] L. Corrado, A. Ratti, C. Gellera, E. Buratti, B. Castellotti, Y. Carlomagnoet al., "High frequency oftardbpgene mutations in italian patients with amyotrophic lateral sclerosis", Human Mutation, vol. 30, no. 4, p. 688-694, 2009. https://doi.org/10.1002/humu.20950
[8] J. Dou, "Tdp-43: a key of neurodegenerative disease", Asian Journal of Complementary and Alternative Medicine, vol. 10, no. 3, 2022. https://doi.org/10.53043/2347-3894.acam90039
[9] C. Hewamadduma, A. Grierson, P. Taylur, L. Pan, C. Moens, P. Inghamet al., "Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish", Human Molecular Genetics, vol. 22, no. 12, p. 2376-2386, 2013. https://doi.org/10.1093/hmg/ddt082
[10] C. Sephton, S. Good, S. Atkin, C. Dewey, P. Mayer, J. Herzet al., "Tdp-43 is a developmentally regulated protein essential for early embryonic development", Journal of Biological Chemistry, vol. 285, no. 9, p. 6826-6834, 2010. https://doi.org/10.1074/jbc.m109.061846
[11] Y. Koike, A. Sugai, N. Hara, J. Ito, A. Yokoseki, T. Ishiharaet al., "Age-related demethylation of the tdp-43 autoregulatory region in the human motor cortex",, 2021. https://doi.org/10.1101/2021.01.13.426599
[12] B. Chitramuthu, D. Kay, A. Bateman, & H. Bennett, "Neurotrophic effects of progranulin in vivo in reversing motor neuron defects caused by over or under expression of tdp-43 or fus", Plos One, vol. 12, no. 3, p. e0174784, 2017. https://doi.org/10.1371/journal.pone.0174784
[13] B. Schmid, A. Hruscha, S. Hogl, J. Banzhaf-Strathmann, K. Strecker, J. Zeeet al., "Loss of als-associated tdp-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth", Proceedings of the National Academy of Sciences, vol. 110, no. 13, p. 4986-4991, 2013. https://doi.org/10.1073/pnas.1218311110
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