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Review

TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target

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Pages 575-592 | Received 03 Apr 2022, Accepted 26 May 2022, Published online: 02 Jun 2022

References

  • Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–133.
  • Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351:602–611.
  • Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2020;383:109–119.
  • Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, et al. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med. 2022;28:104–116.
  • Liu Y, Andreucci A, Iwamoto N, et al. Preclinical evaluation of WVE-004, an investigational stereopure oligonucleotide for the treatment of C9orf72-associated ALS or FTD. Mol Ther. 2022;28:558–570.
  • Narayanan RK, Mangelsdorf M, Panwar A, et al. Identification of RNA bound to the TDP-43 ribonucleoprotein complex in the adult mouse brain. Amyotrophic Lateral Sclerosis Frontotemp Degener. 2013;14:252–260.
  • Sugai A, Kato T, Koyama A, et al. Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation. Neurobiol Dis. 2019;130:104534.
  • Wang A, Conicella AE, Schmidt HB, et al. A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing. EMBO J. 2018;37:e97452.
  • Furukawa Y, Suzuki Y, Fukuoka M, et al. A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43. Sci Rep. 2016;6:20576.
  • Zacco E, Martin SR, Thorogate R, et al. The RNA-recognition motifs of TAR DNA-binding protein 43 may play a role in the aberrant self-assembly of the protein. Front Mol Neurosci. 2018;11:372.
  • Dhakal S, Wyant CE, George HE, et al. Prion-like C-terminal domain of TDP-43 and α-synuclein interact synergistically to generate neurotoxic hybrid fibrils. J Mol Biol. 2021;433:166953.
  • Ishiguro A, Kimura N, Noma T, et al. Molecular dissection of ALS‐linked TDP‐43 – involvement of the Gly‐rich domain in interaction with G‐quadruplex mRNA. FEBS Lett. 2020;594:2254–2265.
  • Zhang Y-J, Xu Y-F, Cook C, et al. Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci. 2009;106:7607–7612.
  • Hergesheimer RC, Chami AA, de Assis DR, et al. The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight? Brain. 2019;142:1176–1194.
  • Morera AA, Ahmed NS, Schwartz JC. TDP-43 regulates transcription at protein-coding genes and Alu retrotransposons. Biochim Biophys Acta. 2019;1862:194434.
  • Mitra J, Guerrero EN, Hegde PM, et al. Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proc Natl Acad Sci USA. 2019;116:4696–4705.
  • Keihani S, Kluever V, Mandad S, et al. The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43. Sci Adv. 2019;5:eaay2670.
  • Kawahara Y, Mieda-Sato A. TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci. 2012;109:3347–3352.
  • Gao J, Wang L, Ren X, et al. Translational regulation in the brain by TDP-43 phase separation. J Cell Biol. 2021;220:e202101019.
  • Ling S-C. Synaptic paths to neurodegeneration: the emerging role of TDP-43 and FUS in synaptic functions. Neural Plast. 2018;2018:1–13.
  • Cathcart SJ, Appel SH, Peterson LE, et al. Fast progression in amyotrophic lateral sclerosis is associated with greater TDP-43 burden in spinal cord. J Neuropathol Exp Neurol. 2021;80:754–763.
  • Johnson BS, Snead D, Lee JJ, et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem. 2009;284:20329–20339.
  • Hawley ZCE, Campos-Melo D, Strong MJ. Evidence of A negative feedback network between TDP-43 and miRNAs dependent on TDP-43 nuclear localization. J Mol Biol. 2020;432:166695.
  • Kim HJ, Taylor JP. Lost in transportation: nucleocytoplasmic transport defects in ALS and other neurodegenerative diseases. Neuron. 2017;96:285–297.
  • Chou -C-C, Zhang Y, Umoh ME, et al. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci. 2018;21:228–239.
  • Anderson EN, Morera AA, Kour S, et al. Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology. eLife. 2021;10:e67587.
  • Watanabe S, Kaneko K, Yamanaka K. Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins. J Biol Chem. 2013;288:3641–3654.
  • Watanabe Y, Taguchi K, Tanaka M. Ubiquitin, autophagy neurodegener dis. Cells. 2020;9:2022.
  • Wang P, Deng J, Dong J, et al. TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genet. 2019;15:e1007947.
  • Dafinca R, Barbagallo P, Talbot K. The role of mitochondrial dysfunction and ER stress in TDP-43 and C9ORF72 ALS. Front Cell Neurosci. 2021;15:653688.
  • Pirie E, Oh C, Zhang X, et al. S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD. Proc Natl Acad Sci USA. 2021;118:e2021368118.
  • Floare M-L, Allen SP. Why TDP-43? Why not? Mechanisms of metabolic dysfunction in amyotrophic lateral sclerosis. J Exp Neurosci. 2020;15:263310552095730.
  • Gautam M, Gunay A, Chandel NS, et al. Mitochondrial dysregulation occurs early in ALS motor cortex with TDP-43 pathology and suggests maintaining NAD+ balance as a therapeutic strategy. Sci Rep. 2022;12:4287.
  • Smethurst P, Newcombe J, Troakes C, et al. In vitro prion-like behaviour of TDP-43 in ALS. Neurobiol Dis. 2016;96:236–247.
  • Ding X, Xiang Z, Qin C, et al. Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice. Acta Neuropathol Commun. 2021;9:15.
  • Chen P-C, Wu D, Hu C-J, et al. Exosomal TAR DNA-binding protein-43 and neurofilaments in plasma of amyotrophic lateral sclerosis patients: a longitudinal follow-up study. J Neurol Sci. 2020;418:117070.
  • Schulthess I, Gorges M, Müller H-P, et al. Functional connectivity changes resemble patterns of pTDP-43 pathology in amyotrophic lateral sclerosis. Sci Rep. 2016;6:38391.
  • Braak H, Ludolph AC, Neumann M, et al. Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic lateral sclerosis. Acta Neuropathol. 2017;133:79–90.
  • Barmada SJ, Serio A, Arjun A, et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014;10:677–685.
  • Zhao T, Hong Y, Yin P, et al. Differential HspBP1 expression accounts for the greater vulnerability of neurons than astrocytes to misfolded proteins. Proc Natl Acad Sci USA. 2017;114:E7803–E7811.
  • Asakawa K, Handa H, Kawakami K. Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons. Nat Commun. 2020;11:1004.
  • Polymenidou M, Lagier-Tourenne C, Hutt KR, et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci. 2011;14:459–468.
  • Pan Y, Nicolazzo JA. Altered blood–brain barrier and blood–spinal cord barrier dynamics in amyotrophic lateral sclerosis: impact on medication efficacy and safety. Br J Pharmacol. 2022;2022:15802.
  • Zamudio F, Loon AR, Smeltzer S, et al. TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model. J Neuroinflammation. 2020;17:283.
  • Ferrer I, Andrés-Benito P, Carmona M, et al. TDP-43 vasculopathy in the spinal cord in sporadic Amyotrophic Lateral Sclerosis (sALS) and frontal cortex in sALS/FTLD-TDP. J Neuropathol Exp Neurol. 2021;80:229–239.
  • Riva N, Gentile F, Cerri F, et al. Phosphorylated TDP-43 aggregates in peripheral motor nerves of patients with amyotrophic lateral sclerosis. Brain. 2022;2022:awab285.
  • Cykowski MD, Powell SZ, Appel JW, et al. Phosphorylated TDP-43 (pTDP-43) aggregates in the axial skeletal muscle of patients with sporadic and familial amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2018;6:28.
  • Wang P, Wander CM, Yuan C-X, et al. Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program. Nat Commun. 2017;8:82.
  • Guo Y, Wang Q, Zhang K, et al. HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 2012;1460:88–95.
  • Iguchi Y, Katsuno M, Niwa J, et al. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain. 2013;136:1371–1382.
  • Grese ZR, Bastos AC, Mamede LD, et al. Specific RNA interactions promote TDP‐43 multivalent phase separation and maintain liquid properties. EMBO Rep. 2021;22:e53632.
  • Rengifo-Gonzalez JC, El Hage K, Clément M-J, et al. The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation. eLife. 2021;10:e67605.
  • Zacco E, Graña-Montes R, Martin SR, et al. RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43. J Mol Biol. 2019;431:1671–1688.
  • Chen H-J, Topp SD, Hui HS, et al. RRM adjacent TARDBP mutations disrupt RNA binding and enhance TDP-43 proteinopathy. Brain. 2019;142:3753–3770.
  • French RL, Grese ZR, Aligireddy H, et al. Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation. J Biol Chem. 2019;294:6696–6709.
  • Flores BN, Li X, Malik AM, et al. An intramolecular salt bridge linking TDP43 RNA binding, protein stability, and TDP43-dependent neurodegeneration. Cell Rep. 2019;27:1133–1150.e8.
  • François-Moutal L, Felemban R, Scott DD, et al. Small molecule targeting TDP-43ʹs RNA recognition motifs reduces locomotor defects in a drosophila model of Amyotrophic Lateral Sclerosis (ALS). ACS Chem Biol. 2019;14:2006–2013.
  • Mollasalehi N, Francois-Moutal L, Scott DD, et al. An allosteric modulator of RNA binding targeting the N-terminal domain of TDP-43 yields neuroprotective properties. ACS Chem Biol. 2020;15:2854–2859.
  • Nana AL, Sidhu M, Gaus SE, et al. Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology. Acta Neuropathol. 2019;137:27–46.
  • Ling JP, Pletnikova O, Troncoso JC, et al. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science. 2015;349:650–655.
  • Melamed Z, López-Erauskin J, Baughn MW, et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci. 2019;22:180–190.
  • Brown A-L, Wilkins OG, Keuss MJ, et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature. 2022;603:131–137.
  • Haines JD, Herbin O, de la Hera B, et al. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nat Neurosci. 2015;18:511–520.
  • Archbold HC, Jackson KL, Arora A, et al. TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia. Sci Rep. 2018;8:4606.
  • Pinarbasi ES, Cağatay T, Fung HYJ, et al. Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization. Sci Rep. 2018;8:7083.
  • Park JH, Chung CG, Park SS, et al. Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3. eLife. 2020;9:e60132.
  • Guo L, Kim HJ, Wang H, et al. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell. 2018;173:677–692.e20.
  • Odeh HM, Fare CM, Shorter J. Nuclear-import receptors counter deleterious phase transitions in neurodegenerative disease. J Mol Biol. 2022;434:167220.
  • Jackrel ME, DeSantis ME, Martinez BA, et al. Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell. 2014;156:170–182.
  • Bharathi V, Bajpai A, Parappuram IT, et al. Elevated constitutive expression of Hsp40 chaperone Sis1 reduces TDP-43 aggregation-induced oxidative stress in Ire1 pathway dependent-manner in yeast TDP-43 proteinopathy model of amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2022;595:28–34.
  • Crippa V, Cicardi ME, Ramesh N, et al. The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity. Hum Mol Genet. 2016;25:3908–3924.
  • Yu H, Lu S, Gasior K, et al. HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells. Science. 2021;371:eabb4309.
  • Lin LT, Razzaq A, Di Gregorio SE, et al. Hsp90 and its co‐chaperone Sti1 control TDP‐43 misfolding and toxicity. FASEB J. 2021;35:e21594.
  • Chen H-J, Mitchell JC, Novoselov S, et al. The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis. Brain. 2016;139:1417–1432.
  • Benatar M, Wuu J, Andersen PM, et al. Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology. 2018;90:e565–e574.
  • Kuta R, Larochelle N, Fernandez M, et al. Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models. Cell Stress Chaperones. 2020;25:173–191.
  • Gregory JM, Barros TP, Meehan S, et al. The aggregation and neurotoxicity of TDP-43 and its ALS-associated 25 kDa fragment are differentially affected by molecular chaperones in drosophila. PLoS One. 2012;7:e31899.
  • Ormeño F, Hormazabal J, Moreno J, et al. Chaperone mediated autophagy degrades TDP-43 protein and is affected by TDP-43 aggregation. Front Mol Neurosci. 2020;13:19.
  • Jo M, Lee S, Kim K, et al. Inhibition of MEK5 suppresses TDP-43 toxicity via the mTOR-independent activation of the autophagy-lysosome pathway. Biochem Biophys Res Commun. 2019;513:925–932.
  • Wang Y, Liu F-T, Wang Y-X, et al. Autophagic modulation by trehalose reduces accumulation of TDP-43 in a cell model of amyotrophic lateral sclerosis via TFEB activation. Neurotox Res. 2018;34:109–120.
  • Chang C-F, Lee Y-C, Lee K-H, et al. Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD and ALS. J Biomed Sci. 2016;23:72.
  • Liu C, Leng B, Li Y, et al. Diallyl trisulfide protects motor neurons from the neurotoxic protein TDP-43 via activating lysosomal degradation and the antioxidant response. Neurochem Res. 2018;43:2304–2312.
  • Wang I-F, Guo B-S, Liu Y-C, et al. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci. 2012;109:15024–15029.
  • Chen Y, Wang H, Ying Z, et al. Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: the new molecular mechanism of ibudilast and its implication for neuroprotective therapy. Biochem Biophys Res Commun. 2020;526:231–238.
  • Kumar S, Phaneuf D, Julien J-P. Withaferin-A treatment alleviates TAR DNA-binding protein-43 pathology and improves cognitive function in a mouse model of FTLD. Neurotherapeutics. 2021;18:286–296.
  • Yin P, Bai D, Deng F, et al. SQSTM1-mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain. Autophagy. 2021;1–14.
  • Crippa V, D’Agostino VG, Cristofani R, et al. Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases. Sci Rep. 2016;6:22827.
  • Mandrioli J, Crippa V, Cereda C, et al. Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS). BMJ Open. 2019;9:e028486.
  • Perera ND, Tomas D, Wanniarachchillage N, et al. Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice. Neurobiol Dis. 2021;154:105359.
  • Liu G, Byrd A, Warner AN, et al. Cdc48/VCP and endocytosis regulate TDP-43 and FUS toxicity and turnover. Mol Cell Biol. 2020;40:e00256–19.
  • Liu G, Coyne AN, Pei F, et al. Endocytosis regulates TDP-43 toxicity and turnover. Nat Commun. 2017;8:2092.
  • Tashiro Y, Urushitani M, Inoue H, et al. Motor neuron-specific disruption of proteasomes, but not autophagy, replicates amyotrophic lateral sclerosis. J Biol Chem. 2012;287:42984–42994.
  • Chou -C-C, Alexeeva OM, Yamada S, et al. PABPN1 suppresses TDP-43 toxicity in ALS disease models. Hum Mol Genet. 2015;24:5154–5173.
  • Cragnaz L, Spinelli G, De Conti L, et al. Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance. Neurobiol Dis. 2021;160:105515.
  • Tamaki Y, Shodai A, Morimura T, et al. Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody with dual proteolytic signals. Sci Rep. 2018;8:6030.
  • Pozzi S, Thammisetty SS, Codron P, et al. Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology. J Clin Investig. 2019;129:1581–1595.
  • Zhao B, Louadi S, Dijkstra AA, et al. Selective targeting of intracellular, misfolded, pathogenic TDP‐43 with rationally designed intrabodies. Alzheimers Dement. 2021;17:e045221.
  • Gilodi M, Lisi S, Dudás F, et al. Selection and modelling of a new single-domain intrabody against TDP-43. Front Mol Biosci. 2022;8:773234.
  • Li Q, Babinchak WM, Surewicz WK. Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43. Nat Commun. 2021;12:1620.
  • Scotter EL, Vance C, Nishimura AL, et al. Differential roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of soluble and aggregated TDP-43 species. J Cell Sci. 2014;127:1263–1278.
  • Zhang Y, Gu J, Sun Q. Aberrant stress granule dynamics and aggrephagy in ALS pathogenesis. Cells. 2021;10:2247.
  • Ratti A, Gumina V, Lenzi P, et al. Chronic stress induces formation of stress granules and pathological TDP-43 aggregates in human ALS fibroblasts and iPSC-motoneurons. Neurobiol Dis. 2020;145:105051.
  • McGurk L, Gomes E, Guo L, et al. Poly(ADP-Ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol Cell. 2018;71:703–717.e9.
  • Moujalled D, James JL, Yang S, et al. Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43. Human Mol Genet. 2015;24:1655–1669.
  • Kim H-J, Raphael AR, LaDow ES, et al. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. 2014;46:152–160.
  • Fang MY, Markmiller S, Vu AQ, et al. Small-molecule modulation of TDP-43 recruitment to stress granules prevents persistent TDP-43 accumulation in ALS/FTD. Neuron. 2019;103:802–819.e11.
  • Becker LA, Huang B, Bieri G, et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017;544:367–371.
  • Fernandes N, Nero L, Lyons S, et al. Stress granule assembly can facilitate but is not required for TDP-43 cytoplasmic aggregation. Biomolecules. 2020;10:1367.
  • Zhang Y-J, Gendron TF, Xu Y-F, et al. Phosphorylation regulates proteasomal-mediated degradation and solubility of TAR DNA binding protein-43 C-terminal fragments. Mol Neurodegeneration. 2010;5:33.
  • Martínez-González L, Gonzalo-Consuegra C, Gómez-Almería M, et al. Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis. IJMS. 2021;22:8975.
  • Rojas-Prats E, Martinez-Gonzalez L, Gonzalo-Consuegra C, et al. Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: a new therapeutic approach for amyotrophic lateral sclerosis. Eur J Med Chem. 2021;210:112968.
  • Vaca G, Martinez‐Gonzalez L, Fernandez A, et al. Therapeutic potential of novel Cell Division Cycle Kinase 7 inhibitors on TDP‐43‐related pathogenesis such as Frontotemporal Lobar Degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). J Neurochem. 2021;156:379–390.
  • Martínez-González L, Rodríguez-Cueto C, Cabezudo D, et al. Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment. Sci Rep. 2020;10:4449.
  • Nozal V, Martínez-González L, Gomez-Almeria M, et al. TDP-43 modulation by Tau-Tubulin kinase 1 inhibitors: a new avenue for future amyotrophic lateral sclerosis therapy. J Med Chem. 2022;65:1585–1607.
  • Yin P, Guo X, Yang W, et al. Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains. Acta Neuropathol. 2019;137:919–937.
  • Farrawell NE, Lambert-Smith IA, Warraich ST, et al. Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions. Sci Rep. 2015;5:13416.
  • Bonifacino T, Zerbo RA, Balbi M, et al. Nearly 30 years of animal models to study amyotrophic lateral sclerosis: a historical overview and future perspectives. IJMS. 2021;22:12236.
  • Spiller KJ, Cheung CJ, Restrepo CR, et al. Selective motor neuron resistance and recovery in a new inducible mouse model of TDP-43 proteinopathy. J Neurosci. 2016;36:7707–7717.
  • Steinacker P, Barschke P, Otto M. Biomarkers for diseases with TDP-43 pathology. Mol Cell Neurosci. 2019;97:43–59.
  • Baker MR. ALS—dying forward, backward or outward? Nat Rev Neurol. 2014;10:660.
  • Eisen A, Braak H, Del Tredici K, et al. Cortical influences drive amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2017;88:917–924.
  • Scaricamazza S, Salvatori I, Ferri A, et al. Skeletal muscle in ALS: an unappreciated therapeutic opportunity? Cells. 2021;10:525.
  • de Boer EMJ, Orie VK, Williams T, et al. TDP-43 proteinopathies: a new wave of neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2021;92:86–95.

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