The role of TDP-43 protein in amyotrophic lateral sclerosis


  • Piotr Włodarczyk Faculty of Medicine, Poznan University of Medical Sciences, Poland
  • Mikołaj Witczak Faculty of Medicine, Poznan University of Medical Sciences, Poland
  • Agnieszka Gajewska Faculty of Medicine, Poznan University of Medical Sciences, Poland
  • Tomasz Chady Faculty of Medicine, Poznan University of Medical Sciences, Poland
  • Igor Piotrowski Department of Electroradiology, Poznan University of Medical Sciences, Poland; Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Poland



Amyotrophic lateral sclerosis, ALS, TDP-43, SINE, Antisense oligonucleotides, Chaperones, autophagy enhancers


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease where both upper and lower motoneurons are damaged. Even though the pathogenesis of ALS is unclear, the TDP-43 aggregations and non-nuclear localization may be crucial to understanding this process. Despite intensive research on ALS therapies, only two lifespan-prolonging medications have been approved: Riluzole and Edaravone. Unravelling the TDP-43 pathology could help develop new ALS therapies using mechanisms such as inhibition of nuclear export, autophagy, chaperones, or antisense oligonucleotides. Selective inhibitors of nuclear export (SINEs) are drugs that block Exportin 1 (XPO1) and cause the accumulation of not exported molecules inside the nucleus. SINEs that target XPO1 are shown to slightly extend the survival of neurons and soften motor symptoms. Dysfunctional proteins, including TDP-43, can be eliminated through autophagocytosis, which is regulated by the mTOR kinase. Stimulating the elimination of protein deposits may be an effective ALS therapy. Antisense oligonucleotides (ASO) are single-stranded, synthetic oligonucleotides that can bind and modulate specific RNA: via ribonuclease H, inducing their degradation or inducing alternative splicing via blocking primary RNA transcripts.  Current ASOs therapies used in ALS focus on SOD1, C9ORF72, FUS, and ATXN2, and they may be used to slow the ALS progression. Reversing the aggregation is a promising therapeutic strategy. Chaperones control other proteins' quality and protect them against stress factors. Due to the irreversible character of ALS, it is essential to understand its complicated pathology better and to seek new therapies.


Download data is not yet available.


Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377:942-55. DOI:

Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol. 2019;32:771-6. DOI:

Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG, On Behalf of the Eurals Consortium. Prognostic factors in ALS: A critical review. Amyotrophic Lateral Sclerosis. 2009;10:310-323. doi: 10.3109/17482960802566824. DOI:

Benbrika S, Desgranges B, Eustache F, Viader F. Cognitive, Emotional and Psychological Manifestations in Amyotrophic Lateral Sclerosis at Baseline and Overtime: A Review. Front Neurosci. 2019;13:951. DOI:

Ling S‑C, Polymenidou M, Cleveland DW. Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis. Neuron. 2013;79:416-438. doi: 10.1016/j.neuron.2013.07.033.

van Es MA, Hardiman O, Chio A, Al‑Chalabi A, Pasterkamp RJ, Veldink JH, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390:2084-98. DOI:

Nowicka N, Juranek J, Juranek JK, Wojtkiewicz J. Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis. Int J Mol Sci. 2019;20:2616. DOI:

Fang F, Ingre C, Roos P, Kamel F, Piehl F. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol. 2015:181. DOI:

Nguyen HP, Van Broeckhoven C, van der Zee J. ALS Genes in the Genomic Era and their Implications for FTD. Trends Genet. 2018;34:404-23. DOI:

Suk TR, Rousseaux MWC. The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol Neurodegener. 2020;15:45. DOI:

Polymenidou M, Cleveland DW. The Seeds of Neurodegeneration: Prion‑like Spreading in ALS. Cell. 2011;147:498-508. DOI:

Hardiman O, Al‑Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071. DOI:

Ayala YM, Zago P, D’Ambrogio A, Xu Y‑F, Petrucelli L, Buratti E, et al. Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci. 2008;121:3778-85. DOI:

Ling S‑C, Albuquerque CP, Han JS, Lagier‑Tourenne C, Tokunaga S, Zhou H, et al. ALS‑associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci USA. 2010;107:13318-23. DOI:

Aulas A, Vande Velde C. Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS? Front Cell Neurosci. 2015;9. DOI:

Conicella AE, Zerze GH, Mittal J, Fawzi NL. ALS Mutations Disrupt Phase Separation Mediated by α‑Helical Structure in the TDP-43 Low‑Complexity C‑Terminal Domain. Structure. 2016;24:1537-49. DOI:

Carey JL, Guo L. Liquid‑Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases. Front Mol Biosci. 2022;9:826719. doi: 10.3389/fmolb.2022.826719. DOI:

Chiang C‑H, Grauffel C, Wu L‑S, Kuo P‑H, Doudeva LG, Lim C, et al. Structural analysis of disease‑related TDP-43 D169G mutation: linking enhanced stability and caspase cleavage efficiency to protein accumulation. Sci Rep. 2016;6:21581. DOI:

Flores BN, Li X, Malik AM, Martinez J, Beg AA, Barmada SJ. An Intramolecular Salt Bridge Linking TDP43 RNA Binding, Protein Stability, and TDP43-Dependent Neurodegeneration. Cell Rep. 2019;27:1133-1150.e8. DOI:

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science. 2006;314:130-3. DOI:

Maharana S, Wang J, Papadopoulos DK, Richter D, Pozniakovsky A, Poser I, et al. RNA buffers the phase separation behavior of prion‑like RNA binding proteins. Science. 2018;360:918-21. DOI:

Lukavsky PJ, Daujotyte D, Tollervey JR, Ule J, Stuani C, Buratti E, et al. Molecular basis of UG‑rich RNA recognition by the human splicing factor TDP-43. Nat Struct Mol Biol. 2013;20:1443-9. DOI:

Jiang L‑L, Xue W, Hong J‑Y, Zhang J‑T, Li M‑J, Yu S‑N, et al. The N‑terminal dimerization is required for TDP-43 splicing activity. Sci Rep. 2017;7:6196. DOI:

Afroz T, Hock E‑M, Ernst P, Foglieni C, Jambeau M, Gilhespy LAB, et al. Functional and dynamic polymerization of the ALS‑linked protein TDP-43 antagonizes its pathologic aggregation. Nat Commun. 2017;8:45. DOI:

Winton MJ, Van Deerlin VM, Kwong LK, Yuan W, Wood EM, Yu C‑E, et al. A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Lett. 2008;582:2252-6. DOI:

Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7:409-16. DOI:

Santamaria N, Alhothali M, Alfonso MH, Breydo L, Uversky VN. Intrinsic disorder in proteins involved in amyotrophic lateral sclerosis. Cell Mol Life Sci. 2017;74:1297-318. DOI:

Smethurst P, Newcombe J, Troakes C, Simone R, Chen Y‑R, Patani R, et al. In vitro prion‑like behaviour of TDP-43 in ALS. Neurobiol Dis. 2016;96:236-47. DOI:

Fraser PE. Prions and Prion‑like Proteins. Journal of Biological Chemistry. 2014;289:19839-19840. DOI: 10.1074/jbc.R114.583492. DOI:

Lee S, Kim H‑J. Prion‑like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key? Exp Neurobiol. 2015;24:1-7. DOI: 10.5607/en.2015.24.1.1. DOI:

Berning BA, Walker AK. The Pathobiology of TDP-43 C‑Terminal Fragments in ALS and FTLD. Front Neurosci. 2019;13:335. DOI:

Keszycki R, Jamshidi P, Kawles A, Minogue G, Flanagan M, Zaccard C, et al. Propagation of TDP-43 proteinopathy in neurodegenerative disorders. Neural Regen Res. 2022;17:1498. DOI:

Oberstadt M, Stieler J, Simpong DL, Römuß U, Urban N, Schaefer M, et al. TDP-43 self‑interaction is modulated by redox‑active compounds Auranofin, Chelerythrine and Riluzole. Sci Rep. 2018;8:2248. DOI:

Andrews JA, Jackson CE, Heiman‑Patterson TD, Bettica P, Brooks BR, Pioro EP. Real‑world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21:509-18. DOI:

Miller R, Mitchell J, Lyon M, Moore D. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). In: The Cochrane Collaboration, editor. Cochrane Database Syst Rev. 2002, p. CD001447. DOI:

Bissaro M, Federico S, Salmaso V, Sturlese M, Spalluto G, Moro S. Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View? ChemMedChem. 2018;13:2601-5. DOI:

Bissaro M, Moro S. Rethinking to riluzole mechanism of action: the molecular link among protein kinase CK1δ activity, TDP-43 phosphorylation, and amyotrophic lateral sclerosis pharmacological treatment. Neural Regen Res. 2019;14:2083. DOI:

Wright AL, Della Gatta PA, Le S, Berning BA, Mehta P, Jacobs KR, et al. Riluzole does not ameliorate disease caused by cytoplasmic TDP‐43 in a mouse model of amyotrophic lateral sclerosis. Eur J Neurosci. 2021;54:6237-55. DOI:

Amekura S, Shiozawa K, Kiryu C, Yamamoto Y, Fujisawa A. Edaravone, a scavenger for multiple reactive oxygen species, reacts with singlet oxygen to yield 2-oxo-3-(phenylhydrazono)-butanoic acid. J Clin Biochem Nutr. 2022;70:240-7. DOI:

Cha SJ, Kim K. Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection. Antioxidants (Basel). 2022;11:195. DOI:

Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother. 2017;18:735-8. DOI:

Pirie E, Oh C, Zhang X, Han X, Cieplak P, Scott HR, 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. DOI:

Ohta Y, Nomura E, Shang J, Feng T, Huang Y, Liu X, et al. Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis. J Neurosci Res. 2019;97:607-19. DOI:

Moujalled D, Grubman A, Acevedo K, Yang S, Ke YD, Moujalled DM, Duncan C, Caragounis A, Perera ND, Turner BJ, et al. TDP-43 mutations causing amyotrophic lateral sclerosis are associated with altered expression of RNA‑binding protein hnRNP K and affect the Nrf2 antioxidant pathway. Human Molecular Genetics. 2017;26:1732-1746. DOI: 10.1093/hmg/ddx093. DOI:

Brooks BR, Heiman‑Patterson T, Wiedau‑Pazos M, Liu S, Zhang J, Apple S. Edaravone efficacy in amyotrophic lateral sclerosis with reduced forced vital capacity: Post‑hoc analysis of Study 19 (MCI186-19) [clinical trial NCT01492686]. PLoS ONE. 2022;17:e0258614. DOI:

Fischer U, Huber J, Boelens WC, Mattajt LW, Lührmann R. The HIV-1 Rev Activation Domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell. 1995;82:475-83. DOI:

Wen W, Meinkotht JL, Tsien RY, Taylor SS. Identification of a signal for rapid export of proteins from the nucleus. Cell. 1995;82:463-73. DOI:

Green AL, Ramkissoon SH, McCauley D, Jones K, Perry JA, Hsu JH‑R, et al. Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma. Neuro Oncol. 2015;17:697-707. DOI:

Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral Selinexor–Dexamethasone for Triple‑Class Refractory Multiple Myeloma. N Engl J Med. 2019;381:727-38. DOI:

Silvestrini MJ, Johnson JR, Kumar AV, Thakurta TG, Blais K, Neill ZA, et al. Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan. Cell Rep. 2018;23:1915-21. DOI:

Archbold HC, Jackson KL, Arora A, Weskamp K, Tank EM‑H, Li X, et al. TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia. Sci Rep. 2018;8:4606. DOI:

Pinarbasi ES, Cağatay T, Fung HYJ, Li YC, Chook YM, Thomas PJ. Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization. Sci Rep. 2018;8:7083. DOI:

Herceg Z, Wang Z‑Q. Functions of poly(ADP‑ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res. 2001;477:97-110. DOI:

Martire S, Mosca L, d’Erme M. PARP-1 involvement in neurodegeneration: A focus on Alzheimer’s and Parkinson’s diseases. Mech Ageing Dev. 2015;146-148:53-64. DOI:

Duan Y, Du A, Gu J, Duan G, Wang C, Gui X, et al. PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease‑related RNA‑binding proteins. Cell Res. 2019;29:233-47. DOI:

Kim HJ, Kim NC, Wang Y‑D, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion‑like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467-73. DOI:

Chen S, Zhang X, Song L, Le W. Autophagy Dysregulation in Amyotrophic Lateral Sclerosis: Autophagy Dysregulation in ALS. Brain Pathol. 2012;22:110-6. DOI:

Chua JP, De Calbiac H, Kabashi E, Barmada SJ. Autophagy and ALS: mechanistic insights and therapeutic implications. Autophagy. 2022;18:254-82. DOI:

Palomo V, Nozal V, Rojas‐Prats E, Gil C, Martinez A. Protein kinase inhibitors for amyotrophic lateral sclerosis therapy. Br J Pharmacol. 2021;178:1316-35.

Mandrioli J, D’Amico R, Zucchi E, Gessani A, Fini N, Fasano A, et al. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double‑blind, placebo‑controlled, multicenter, clinical trial (RAP‑ALS trial). Medicine (Baltimore). 2018;97:e11119.

Wang Y, Liu F‑T, Wang Y‑X, Guan R‑Y, Chen C, Li D‑K, 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;34:109-20. DOI:

Rusmini P, Cortese K, Crippa V, Cristofani R, Cicardi ME, Ferrari V, et al. Trehalose induces autophagy via lysosomal‑mediated TFEB activation in models of motoneuron degeneration. Autophagy. 2019;15:631-51. DOI:

van Eijk RPA, Jones AR, Sproviero W, Shatunov A, Shaw PJ, Leigh PN, et al. Meta‑analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials. Neurology. 2017;89:1915-22. DOI:

Amado DA, Davidson BL. Gene therapy for ALS: A review. Mol. Ther. 2021;29:3345-58. DOI:

Xue YC, Ng CS, Xiang P, Liu H, Zhang K, Mohamud Y, et al. Dysregulation of RNA‑Binding Proteins in Amyotrophic Lateral Sclerosis. Front Mol Neurosci. 2020;13:78. DOI:

Scoles DR, Pulst SM. Oligonucleotide therapeutics in neurodegenerative diseases. RNA Biol. 2018:1-8. DOI:

Farrawell NE, Lambert‑Smith IA, Warraich ST, Blair IP, Saunders DN, Hatters DM, et al. Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions. Sci Rep. 2015;5:13416. DOI:

Zeineddine R, Farrawell NE, Lambert‑Smith IA, Yerbury JJ. Addition of exogenous SOD1 aggregates causes TDP-43 mislocalization and aggregation. Cell Stress Chaperones. 2017;22:893-902. DOI:

Jeon GS, Shim Y‑M, Lee D‑Y, Kim J‑S, Kang M, Ahn SH, et al. Pathological Modification of TDP-43 in Amyotrophic Lateral Sclerosis with SOD1 Mutations. Mol Neurobiol. 2019;56:2007-21. DOI:

Cappella M, Pradat P‑F, Querin G, Biferi MG. Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy. J Neuromuscul Dis. 2021;8:25-38. DOI:

Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, et al. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020;383:109-19. DOI:

Colombrita C, Onesto E, Megiorni F, Pizzuti A, Baralle FE, Buratti E, et al. TDP-43 and FUS RNA‑binding Proteins Bind Distinct Sets of Cytoplasmic Messenger RNAs and Differently Regulate Their Post‑transcriptional Fate in Motoneuron‑like Cells. J Biol Chem. 2012;287:15635-47. DOI:

Hübers A, Just W, Rosenbohm A, Müller K, Marroquin N, Goebel I, et al. De novo FUS mutations are the most frequent genetic cause in early‑onset German ALS patients. Neurobiol Aging. 2015;36:3117.e1-3117.e6. DOI:

Korobeynikov VA, Lyashchenko AK, Blanco‑Redondo B, Jafar‑Nejad P, Shneider NA. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med. 2022;28:104-16. DOI:

Codron P, Cassereau J, Vourc’h P. InFUSing antisense oligonucleotides for treating ALS. Trends Mol Med. 2022;28:253-4. DOI:

Konopka A, Atkin J. The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis. Int J Mol Sci. 2018;19:3137. DOI:

Cook CN, Wu Y, Odeh HM, Gendron TF, Jansen‑West K, del Rosso G, et al. C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy. Sci Transl Med. 2020;12:eabb3774. DOI:

Vatsavayai SC, Nana AL, Yokoyama JS, Seeley WW. C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies. Acta Neuropathol. 2019;137:1-26. DOI:

Liu Y, Andreucci A, Iwamoto N, Yin Y, Yang H, Liu F, et al. Preclinical evaluation of WVE-004, an investigational stereo pure oligonucleotide for the treatment of C9orf72-associated ALS or FTD. Mol Ther Nucleic Acids. 2022;28:558-70. DOI:

Elden AC, Kim H‑J, Hart MP, Chen‑Plotkin AS, Johnson BS, Fang X, et al. Ataxin-2 intermediate‑length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466:1069-75. DOI:

Lee T, Li YR, Ingre C, Weber M, Grehl T, Gredal O, et al. Ataxin-2 intermediate‑length polyglutamine expansions in European ALS patients. Hum Mol Genet. 2011;20:1697-700. DOI:

Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar‑Nejad P, et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017;544:367-71. DOI:

Hart MP, Gitler AD. ALS‑Associated Ataxin 2 PolyQ Expansions Enhance Stress‑Induced Caspase 3 Activation and Increase TDP-43 Pathological Modifications. J Neurosci. 2012;32:9133-42. DOI:

Ling S‑C, Polymenidou M, Cleveland DW. Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis. Neuron. 2013;79:416-38. DOI:

Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. TDP-43 Is Intrinsically Aggregation‑prone, and Amyotrophic Lateral Sclerosis‑linked Mutations Accelerate Aggregation and Increase Toxicity. J Biol Chem. 2009;284:20329-39. DOI:

Kim Y, Park J‑H, Jang J‑Y, Rhim H, Kang S. Characterization and Hsp104-induced artificial clearance of familial ALS‑related SOD1 aggregates. Biochem Biophys Res Commun. 2013;434:521-6. DOI:

Kalmar B, Lu C‑H, Greensmith L. The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol. Pharmacol Ther. 2014;141:40-54. DOI:

Wang P, Wander CM, Yuan C‑X, Bereman MS, Cohen TJ. Acetylation‑induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program. Nat Commun. 2017;8:82. DOI:

Lin P‑Y, Folorunso O, Taglialatela G, Pierce A. Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells: HSF1 Maintains TDP-43 Solubility. J Neurosci Res. 2016;94:671-82. DOI:

François‑Moutal L, Scott DD, Ambrose AJ, Zerio CJ, Rodriguez‑Sanchez M, Dissanayake K, et al. Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology. Sci Rep. 2022;12:8140. DOI:

Lin LT, Razzaq A, Di Gregorio SE, Hong S, Charles B, Lopes MH, et al. Hsp90 and its co‐chaperone Sti1 control TDP‐43 misfolding and toxicity. FASEB J. 2021;35. DOI:

Ormeño F, Hormazabal J, Moreno J, Riquelme F, Rios J, Criollo A, et al. Chaperone Mediated Autophagy Degrades TDP-43 Protein and Is Affected by TDP-43 Aggregation. Front Mol Neurosci. 2020;13:19. DOI:

Nagy M, Fenton WA, Li D, Furtak K, Horwich AL. Extended survival of misfolded G85R SOD1-linked ALS mice by transgenic expression of chaperone Hsp110. Proc Natl Acad Sci USA. 2016;113:5424-8. DOI:

Luecke IW, Lin G, Santarriaga S, Scaglione KM, Ebert AD. Viral vector gene delivery of the novel chaperone protein SRCP1 to modify insoluble protein in in vitro and in vivo models of ALS. Gene Ther. 2021. DOI:

Tamaki Y, Shodai A, Morimura T, Hikiami R, Minamiyama S, Ayaki T, Tooyama I, Furukawa Y, Takahashi R, Urushitani M. Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding‑specific intrabody with dual proteolytic signals. Sci Rep. 2018;8:6030. DOI: 10.1038/s41598-018-24463-3. DOI:

Pozzi S, Thammisetty SS, Codron P, Rahimian R, Plourde KV, Soucy G, Bareil C, Phaneuf D, Kriz J, Gravel C, et al. Virus‑mediated delivery of antibody targeting TAR DNA‑binding protein-43 mitigates associated neuropathology. Journal of Clinical Investigation. 2019;129:1581-1595. DOI: 10.1172/JCI123931. DOI:

Jaiswal MK. Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs. Med Res Rev. 2019;39:733-748. DOI: 10.1002/med.21528. DOI:

Mandrioli J, D’Amico R, Zucchi E, Gessani A, Fini N, Fasano A, Caponnetto C, Chiò A, Dalla Bella E, Lunetta C, et al. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double‑blind, placebo‑controlled, multicenter, clinical trial (RAP‑ALS trial). Medicine. 2018;97:e11119. DOI: 10.1097/MD.0000000000011119. DOI:

Paganoni S, Hendrix S, Dickson SP, Knowlton N, Macklin EA, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, et al. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle and Nerve. 2021;63:31-39. DOI: 10.1002/mus.27091. DOI:

Palomo V, Nozal V, Rojas-Prats E, Gil C, Martinez A. Protein kinase inhibitors for amyotrophic lateral sclerosis therapy. Br J Pharmacol. 2021;178:1316-1335. DOI: 10.1111/bph.15221. DOI:

Mora JS, Bradley WG, Chaverri D, Hernández‑Barral M, Mascias J, Gamez J, Gargiulo‑Monachelli GM, Moussy A, Mansfield CD, Hermine O, et al. Long‑term survival analysis of masitinib in amyotrophic lateral sclerosis. Ther Adv Neurol Disord. 2021;14:175628642110303. DOI: 10.1177/17562864211030365. DOI:

Shefner JM, Andrews JA, Genge A, Jackson C, Lechtzin N, Miller TM, Cockroft BM, Meng L, Wei J, Wolff AA, et al. A Phase 2, Double‑Blind, Randomized, Dose‑Ranging Trial Of Reldesemtiv In Patients With ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2021;22:287-299. DOI: 10.1080/21678421.2020.1822410. DOI:

Gothelf Y, Abramov N, Harel A, Offen D. Safety of repeated transplantations of neurotrophic factors‐secreting human mesenchymal stromal stem cells. Clinical and Translational Medicine [Internet]. 2014 [cited 2022 Oct 15];3. DOI: 10.1186/2001-1326-3-21. DOI:

Cudkowicz ME, Lindborg SR, Goyal NA, Miller RG, Burford MJ, Berry JD, Nicholson KA, Mozaffar T, Katz JS, Jenkins LJ, et al. A randomized placebo‐controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis. Muscle and Nerve. 2022;65:291-302. DOI: 10.1002/mus.27472. DOI:

Gittings LM, Sattler R. Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies. Fac Rev [Internet]. 2020 [cited 2022 Oct 15];9. DOI: 10.12703/b/9-12. DOI:

How to Cite

Włodarczyk P, Witczak M, Gajewska A, Chady T, Piotrowski I. The role of TDP-43 protein in amyotrophic lateral sclerosis. JMS [Internet]. 2022 Dec. 30 [cited 2023 Feb. 4];91(4):e710. Available from:



Review Papers
Received 2022-07-21
Accepted 2022-11-09
Published 2022-12-30