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The Role of TDP-43 in Neurodegenerative Disease

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Abstract

In recent years, more and more neurodegenerative diseases, such as ALS, FTLD and AD, have been found to share a common pathological feature, which is the depletion of TDP-43 in the nucleus and the accumulation of TDP-43 in the cytoplasm through hyperphosphorylation, ubiquitination and cleavage. Therefore, this kind of neurodegenerative disease is also called TDP-43 proteinopathy. This suggests that TDP-43 plays a role in the pathogenesis of disease. Current studies show that the pathophysiological mechanism of TDP-43 in neurodegeneration is very complex. In this review, we describe the structure of TDP-43, its main physiological functions, the possible pathogenesis and how TDP-43 provides a new pathway to treat neurodegenerative diseases.

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References

  1. Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG et al (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci 21(2):228–239. https://doi.org/10.1038/s41593-017-0047-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Scotter EL, Chen HJ, Shaw CE (2015) TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets. Neurotherapeutics 12(2):352–363. https://doi.org/10.1007/s13311-015-0338-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang T, Mullane PC, Periz G, Wang J (2011) TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling. Hum Mol Genet 20(10):1952–1965. https://doi.org/10.1093/hmg/ddr076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chang JC, Morton DB (2017) Drosophila lines with mutant and wild type human TDP-43 replacing the endogenous gene reveals phosphorylation and ubiquitination in mutant lines in the absence of viability or lifespan defects. PLoS ONE 12(7):e0180828. https://doi.org/10.1371/journal.pone.0180828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13:867–878. https://doi.org/10.2741/2727

    Article  CAS  PubMed  Google Scholar 

  6. Palomo V, Tosat-Bitrian C, Nozal V, Nagaraj S, Martin-Requero A, Martinez A (2019) TDP-43: A Key Therapeutic Target beyond Amyotrophic Lateral Sclerosis. ACS Chem Neurosci 10(3):1183–1196. https://doi.org/10.1021/acschemneuro.9b00026

    Article  CAS  PubMed  Google Scholar 

  7. Birsa N, Bentham MP, Fratta P (2020) Cytoplasmic functions of TDP-43 and FUS and their role in ALS. Semin Cell Dev Biol 99:193–201. https://doi.org/10.1016/j.semcdb.2019.05.023

    Article  CAS  PubMed  Google Scholar 

  8. Zhang N, Gu D, Meng M, Gordon ML (2020) TDP-43 Is Elevated in Plasma Neuronal-Derived Exosomes of Patients With Alzheimer’s Disease. Front Aging Neurosci 12:166. https://doi.org/10.3389/fnagi.2020.00166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sleigh JN, Tosolini AP, Gordon D, Devoy A, Fratta P, Fisher EMC, Talbot K, Schiavo G (2020) Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes. Cell Rep 30(11):3655-3662.e3652. https://doi.org/10.1016/j.celrep.2020.02.078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim T, Song B, Lee IS (2020) Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders. Int J Mol Sci 21 (14). doi:https://doi.org/10.3390/ijms21144859

  11. Clark JA, Yeaman EJ, Blizzard CA, Chuckowree JA, Dickson TC (2016) A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease. Front Cell Neurosci 10:204. https://doi.org/10.3389/fncel.2016.00204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Terry DM, Devine SE (2019) Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders. Front Genet 10:1244. https://doi.org/10.3389/fgene.2019.01244

    Article  CAS  PubMed  Google Scholar 

  13. Ayala YM, Zago P, D’Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE (2008) Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121(Pt 22):3778–3785. https://doi.org/10.1242/jcs.038950

    Article  CAS  PubMed  Google Scholar 

  14. Darling AL (1868) Shorter J (2021) Combating deleterious phase transitions in neurodegenerative disease. Biochim Biophys Acta Mol Cell Res 5:118984. https://doi.org/10.1016/j.bbamcr.2021.118984

    Article  CAS  Google Scholar 

  15. Floare ML, Allen SP (2020) Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis. Neurosci Insights 15:2633105520957302. https://doi.org/10.1177/2633105520957302

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wang W, Wang L, Lu J, Siedlak SL, Fujioka H, Liang J, Jiang S, Ma X et al (2016) The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med 22(8):869–878. https://doi.org/10.1038/nm.4130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hergesheimer RC, Chami AA, de Assis DR, Vourc’h P, Andres CR, Corcia P, Lanznaster D, Blasco H (2019) The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight? Brain 142(5):1176–1194. https://doi.org/10.1093/brain/awz078

    Article  PubMed  PubMed Central  Google Scholar 

  18. Buratti E (2020) Targeting TDP-43 proteinopathy with drugs and drug-like small molecules. Br J Pharmacol. https://doi.org/10.1111/bph.15148

    Article  PubMed  Google Scholar 

  19. Winton MJ, Igaz LM, Wong MM, Kwong LK, Trojanowski JQ, Lee VM (2008) Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J Biol Chem 283(19):13302–13309. https://doi.org/10.1074/jbc.M800342200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Buratti E, Baralle FE (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J Biol Chem 276(39):36337–36343. https://doi.org/10.1074/jbc.M104236200

    Article  CAS  PubMed  Google Scholar 

  21. Coyne AN, Zaepfel BL, Zarnescu DC (2017) Failure to Deliver and Translate-New Insights into RNA Dysregulation in ALS. Front Cell Neurosci 11:243. https://doi.org/10.3389/fncel.2017.00243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gao FB, Almeida S, Lopez-Gonzalez R (2017) Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. Embo j 36(20):2931–2950. https://doi.org/10.15252/embj.201797568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ratti A, Buratti E (2016) Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem 138(Suppl 1):95–111. https://doi.org/10.1111/jnc.13625

    Article  CAS  PubMed  Google Scholar 

  24. Konopka A, Whelan DR, Jamali MS, Perri E, Shahheydari H, Toth RP, Parakh S, Robinson T et al (2020) Impaired NHEJ repair in amyotrophic lateral sclerosis is associated with TDP-43 mutations. Mol Neurodegener 15(1):51. https://doi.org/10.1186/s13024-020-00386-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Deshaies JE, Shkreta L, Moszczynski AJ, Sidibé H, Semmler S, Fouillen A, Bennett ER, Bekenstein U et al (2018) TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis. Brain 141(5):1320–1333. https://doi.org/10.1093/brain/awy062

    Article  PubMed  PubMed Central  Google Scholar 

  26. Pham J, Keon M, Brennan S, Saksena N (2020) Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy. Int J Mol Sci 21 (10). doi:https://doi.org/10.3390/ijms21103464

  27. Russo A, Scardigli R, La Regina F, Murray ME, Romano N, Dickson DW, Wolozin B, Cattaneo A et al (2017) Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes. Hum Mol Genet 26(8):1407–1418. https://doi.org/10.1093/hmg/ddx035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ayala YM, De Conti L, Avendaño-Vázquez SE, Dhir A, Romano M, D’Ambrogio A, Tollervey J, Ule J et al (2011) TDP-43 regulates its mRNA levels through a negative feedback loop. Embo j 30(2):277–288. https://doi.org/10.1038/emboj.2010.310

    Article  CAS  PubMed  Google Scholar 

  29. Tziortzouda P, Van Den Bosch L, Hirth F (2021) Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation. Nat Rev Neurosci 22(4):197–208. https://doi.org/10.1038/s41583-021-00431-1

    Article  CAS  PubMed  Google Scholar 

  30. Portz B, Lee BL, Shorter J (2021) FUS and TDP-43 Phases in Health and Disease. Trends Biochem Sci. https://doi.org/10.1016/j.tibs.2020.12.005

    Article  PubMed  PubMed Central  Google Scholar 

  31. de Boer EMJ, Orie VK, Williams T, Baker MR, De Oliveira HM, Polvikoski T, Silsby M, Menon P et al (2020) TDP-43 proteinopathies: a new wave of neurodegenerative diseases. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2020-322983

    Article  PubMed  Google Scholar 

  32. McAlary L, Chew YL, Lum JS, Geraghty NJ, Yerbury JJ, Cashman NR (2020) Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises. Front Cell Neurosci 14:581907. https://doi.org/10.3389/fncel.2020.581907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Layalle S, They L, Ourghani S, Raoul C, Soustelle L (2021) Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster. Int J Mol Sci 22 (2). doi:https://doi.org/10.3390/ijms22020904

  34. Ritson GP, Custer SK, Freibaum BD, Guinto JB, Geffel D, Moore J, Tang W, Winton MJ et al (2010) TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci 30(22):7729–7739. https://doi.org/10.1523/jneurosci.5894-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Miguel L, Frébourg T, Campion D, Lecourtois M (2011) Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies. Neurobiol Dis 41(2):398–406. https://doi.org/10.1016/j.nbd.2010.10.007

    Article  CAS  PubMed  Google Scholar 

  36. Li Y, Ray P, Rao EJ, Shi C, Guo W, Chen X, Woodruff EA 3rd, Fushimi K et al (2010) A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci U S A 107(7):3169–3174. https://doi.org/10.1073/pnas.0913602107

    Article  PubMed  PubMed Central  Google Scholar 

  37. Estes PS, Boehringer A, Zwick R, Tang JE, Grigsby B, Zarnescu DC (2011) Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS. Hum Mol Genet 20(12):2308–2321. https://doi.org/10.1093/hmg/ddr124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hazelett DJ, Chang JC, Lakeland DL, Morton DB (2012) Comparison of parallel high-throughput RNA sequencing between knockout of TDP-43 and its overexpression reveals primarily nonreciprocal and nonoverlapping gene expression changes in the central nervous system of Drosophila. G3 (Bethesda) 2 (7):789–802. doi:https://doi.org/10.1534/g3.112.002998

  39. Romano M, Feiguin F, Buratti E (2012) Drosophila Answers to TDP-43 Proteinopathies. J Amino Acids 2012:356081. https://doi.org/10.1155/2012/356081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lu Y, Ferris J, Gao FB (2009) Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain 2:30. https://doi.org/10.1186/1756-6606-2-30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nakagawa Y, Yamada S (2020) A novel hypothesis on metal dyshomeostasis and mitochondrial dysfunction in amyotrophic lateral sclerosis: Potential pathogenetic mechanism and therapeutic implications. Eur J Pharmacol:173737. doi:https://doi.org/10.1016/j.ejphar.2020.173737

  42. Huang C, Yan S, Zhang Z (2020) Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases. Transl Neurodegener 9(1):40. https://doi.org/10.1186/s40035-020-00219-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gao J, Wang L, Huntley ML, Perry G, Wang X (2018) Pathomechanisms of TDP-43 in neurodegeneration. J Neurochem. https://doi.org/10.1111/jnc.14327

    Article  PubMed  PubMed Central  Google Scholar 

  44. Koren SA, Galvis-Escobar S, Abisambra JF (2020) Tau-mediated dysregulation of RNA: Evidence for a common molecular mechanism of toxicity in frontotemporal dementia and other tauopathies. Neurobiol Dis 141:104939. https://doi.org/10.1016/j.nbd.2020.104939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ et al (2017) Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544(7650):367–371. https://doi.org/10.1038/nature22038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schmidt MF, Gan ZY, Komander D, Dewson G (2021) Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities. Cell Death Differ. https://doi.org/10.1038/s41418-020-00706-7

    Article  PubMed  PubMed Central  Google Scholar 

  47. Herrera-Cruz MS, Simmen T (2017) Of yeast, mice and men: MAMs come in two flavors. Biol Direct 12(1):3. https://doi.org/10.1186/s13062-017-0174-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Suk TR, Rousseaux MWC (2020) The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol Neurodegener 15(1):45. https://doi.org/10.1186/s13024-020-00397-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim SH, Shanware NP, Bowler MJ, Tibbetts RS (2010) Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem 285(44):34097–34105. https://doi.org/10.1074/jbc.M110.154831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sanna S, Esposito S, Masala A, Sini P, Nieddu G, Galioto M, Fais M, Iaccarino C et al (2020) HDAC1 inhibition ameliorates TDP-43-induced cell death in vitro and in vivo. Cell Death Dis 11(5):369. https://doi.org/10.1038/s41419-020-2580-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dang M, Song J (2020) ALS-causing D169G mutation disrupts the ATP-binding capacity of TDP-43 RRM1 domain. Biochem Biophys Res Commun 524(2):459–464. https://doi.org/10.1016/j.bbrc.2020.01.122

    Article  CAS  PubMed  Google Scholar 

  52. Prakash A, Kumar V, Banerjee A, Lynn AM, Prasad R (2020) Structural heterogeneity in RNA recognition motif 2 (RRM2) of TAR DNA-binding protein 43 (TDP-43): clue to amyotrophic lateral sclerosis. J Biomol Struct Dyn:1–11. doi:https://doi.org/10.1080/07391102.2020.1714481

  53. Feiler MS, Strobel B, Freischmidt A, Helferich AM, Kappel J, Brewer BM, Li D, Thal DR et al (2015) TDP-43 is intercellularly transmitted across axon terminals. J Cell Biol 211(4):897–911. https://doi.org/10.1083/jcb.201504057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nay K, Smiles WJ, Kaiser J, McAloon LM, Loh K, Galic S, Oakhill JS, Gundlach AL, et al (2021) Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders. Int J Mol Sci 22 (8). doi:https://doi.org/10.3390/ijms22084052

  55. Liu G, Byrd A, Warner AN, Pei F, Basha E, Buchanan A, Buchan JR (2020) Cdc48/VCP and Endocytosis Regulate TDP-43 and FUS Toxicity and Turnover. Mol Cell Biol 40 (4). doi:https://doi.org/10.1128/mcb.00256-19

  56. Nonaka T, Hasegawa M (2020) Prion-like properties of assembled TDP-43. Curr Opin Neurobiol 61:23–28. https://doi.org/10.1016/j.conb.2019.11.018

    Article  CAS  PubMed  Google Scholar 

  57. Smethurst P, Risse E, Tyzack GE, Mitchell JS, Taha DM, Chen YR, Newcombe J, Collinge J et al (2020) Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis. Brain 143(2):430–440. https://doi.org/10.1093/brain/awz419

    Article  PubMed  PubMed Central  Google Scholar 

  58. Iguchi Y, Eid L, Parent M, Soucy G, Bareil C, Riku Y, Kawai K, Takagi S et al (2016) Exosome secretion is a key pathway for clearance of pathological TDP-43. Brain 139(Pt 12):3187–3201. https://doi.org/10.1093/brain/aww237

    Article  PubMed  PubMed Central  Google Scholar 

  59. Pasetto L, Callegaro S, Corbelli A, Fiordaliso F, Ferrara D, Brunelli L, Sestito G, Pastorelli R et al (2021) Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis. Mol Neurodegener 16(1):52. https://doi.org/10.1186/s13024-021-00470-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kusamoto T, Nishihara H (2018) Efficiency breakthrough for radical LEDs. Nature 563(7732):480–481. https://doi.org/10.1038/d41586-018-07394-x

    Article  CAS  PubMed  Google Scholar 

  61. Jan AT, Malik MA, Rahman S, Yeo HR, Lee EJ, Abdullah TS, Choi I (2017) Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal. Front Aging Neurosci 9:317. https://doi.org/10.3389/fnagi.2017.00317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Song L, Pei L, Yao S, Wu Y, Shang Y (2017) NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies. Front Cell Neurosci 11:63. https://doi.org/10.3389/fncel.2017.00063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Henstridge CM, Tzioras M, Paolicelli RC (2019) Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration. Front Cell Neurosci 13:63. https://doi.org/10.3389/fncel.2019.00063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Strohm L, Behrends C (2020) Glia-specific autophagy dysfunction in ALS. Semin Cell Dev Biol 99:172–182. https://doi.org/10.1016/j.semcdb.2019.05.024

    Article  CAS  PubMed  Google Scholar 

  65. Carillo MR, Bertapelle C, Scialò F, Siervo M, Spagnuolo G, Simeone M, Peluso G, Digilio FA (2020) L-Carnitine in Drosophila: A Review. Antioxidants (Basel) 9 (12). doi:https://doi.org/10.3390/antiox9121310

  66. Velebit J, Horvat A, Smolič T, Prpar Mihevc S, Rogelj B, Zorec R, Vardjan N (2020) Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca(2+) signaling and dysregulated cell metabolism. Sci Rep 10(1):6003. https://doi.org/10.1038/s41598-020-62864-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Herzog JJ, Xu W, Deshpande M, Rahman R, Suib H, Rodal AA, Rosbash M, Paradis S (2020) TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression. Proc Natl Acad Sci U S A 117(21):11760–11769. https://doi.org/10.1073/pnas.1917038117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Riku Y (2020) Reappraisal of the anatomical spreading and propagation hypothesis about TDP-43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neuropathology. https://doi.org/10.1111/neup.12644

    Article  PubMed  Google Scholar 

  69. Watanabe S, Oiwa K, Murata Y, Komine O, Sobue A, Endo F, Takahashi E, Yamanaka K (2020) ALS-linked TDP-43(M337V) knock-in mice exhibit splicing deregulation without neurodegeneration. Mol Brain 13(1):8. https://doi.org/10.1186/s13041-020-0550-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cihankaya H, Theiss C, Matschke V (2021) Little Helpers or Mean Rogue-Role of Microglia in Animal Models of Amyotrophic Lateral Sclerosis. Int J Mol Sci 22 (3). doi:https://doi.org/10.3390/ijms22030993

  71. Yamashita S, Ando Y (2015) Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis. Transl Neurodegener 4:13. https://doi.org/10.1186/s40035-015-0036-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323(5918):1208–1211. https://doi.org/10.1126/science.1165942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brettschneider J, Libon DJ, Toledo JB, Xie SX, McCluskey L, Elman L, Geser F, Lee VM et al (2012) Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol 123(3):395–407. https://doi.org/10.1007/s00401-011-0932-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM et al (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74(1):20–38. https://doi.org/10.1002/ana.23937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Brettschneider J, Arai K, Del Tredici K, Toledo JB, Robinson JL, Lee EB, Kuwabara S, Shibuya K et al (2014) TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol 128(3):423–437. https://doi.org/10.1007/s00401-014-1299-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wong P, Ho WY, Yen YC, Sanford E, Ling SC (2020) The vulnerability of motor and frontal cortex-dependent behaviors in mice expressing ALS-linked mutation in TDP-43. Neurobiol Aging 92:43–60. https://doi.org/10.1016/j.neurobiolaging.2020.03.019

    Article  CAS  PubMed  Google Scholar 

  77. Dyer MS, Reale LA, Lewis KE, Walker AK, Dickson TC, Woodhouse A, Blizzard CA (2020) Amyotrophic lateral sclerosis associated mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex. J Neurochem. https://doi.org/10.1111/jnc.15214

    Article  PubMed  Google Scholar 

  78. Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K (2013) Amyotrophic lateral sclerosis–a model of corticofugal axonal spread. Nat Rev Neurol 9(12):708–714. https://doi.org/10.1038/nrneurol.2013.221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shi KY, Mori E, Nizami ZF, Lin Y, Kato M, Xiang S, Wu LC, Ding M et al (2017) Toxic PR(n) poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc Natl Acad Sci U S A 114(7):E1111-e1117. https://doi.org/10.1073/pnas.1620293114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Weskamp K, Barmada SJ (2018) TDP43 and RNA instability in amyotrophic lateral sclerosis. Brain Res 1693(Pt A):67–74. https://doi.org/10.1016/j.brainres.2018.01.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Benussi A, Alberici A, Samra K, Russell LL, Greaves CV, Bocchetta M, Ducharme S, Finger E et al (2021) Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia. Alzheimers Dement. https://doi.org/10.1002/alz.12485

    Article  PubMed  Google Scholar 

  82. Clos AL, Kayed R, Lasagna-Reeves CA (2012) Association of skin with the pathogenesis and treatment of neurodegenerative amyloidosis. Front Neurol 3:5. https://doi.org/10.3389/fneur.2012.00005

    Article  PubMed  PubMed Central  Google Scholar 

  83. Mesulam M (2013) Primary progressive aphasia: A dementia of the language network. Dement Neuropsychol 7(1):2–9. https://doi.org/10.1590/s1980-57642013dn70100002

    Article  PubMed  PubMed Central  Google Scholar 

  84. Bocchetta M, Iglesias Espinosa MDM, Lashley T, Warren JD, Rohrer JD (2020) In vivo staging of frontotemporal lobar degeneration TDP-43 type C pathology. Alzheimers Res Ther 12(1):34. https://doi.org/10.1186/s13195-020-00600-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rohrer JD, Geser F, Zhou J, Gennatas ED, Sidhu M, Trojanowski JQ, Dearmond SJ, Miller BL et al (2010) TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia. Neurology 75(24):2204–2211. https://doi.org/10.1212/WNL.0b013e318202038c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Brettschneider J, Del Tredici K, Irwin DJ, Grossman M, Robinson JL, Toledo JB, Fang L, Van Deerlin VM et al (2014) Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol 127(3):423–439. https://doi.org/10.1007/s00401-013-1238-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Van Schoor E, Koper MJ, Ospitalieri S, Dedeene L, Tomé SO, Vandenberghe R, Brenner D, Otto M et al (2020) Necrosome-positive granulovacuolar degeneration is associated with TDP-43 pathological lesions in the hippocampus of ALS/FTLD cases. Neuropathol Appl Neurobiol. https://doi.org/10.1111/nan.12668

    Article  PubMed  Google Scholar 

  88. Vaca G, Martinez-Gonzalez L, Fernandez A, Rojas-Prats E, Porras G, Cuevas EP, Gil C, Martinez A et al (2020) 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. https://doi.org/10.1111/jnc.15118

    Article  PubMed  Google Scholar 

  89. Zhang YJ, Xu YF, Dickey CA, Buratti E, Baralle F, Bailey R, Pickering-Brown S, Dickson D et al (2007) Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci 27(39):10530–10534. https://doi.org/10.1523/jneurosci.3421-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rademakers R, Neumann M, Mackenzie IR (2012) Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 8(8):423–434. https://doi.org/10.1038/nrneurol.2012.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gu J, Hu W, Tan X, Qu S, Chu D, Gong CX, Iqbal K, Liu F (2020) Elevation of casein kinase 1ε associated with TDP-43 and tau pathologies in Alzheimer’s disease. Brain Pathol 30(2):283–297. https://doi.org/10.1111/bpa.12775

    Article  CAS  PubMed  Google Scholar 

  92. McGrowder DA, Miller F, Vaz K, Nwokocha C, Wilson-Clarke C, Anderson-Cross M, Brown J, Anderson-Jackson L, et al (2021) Cerebrospinal Fluid Biomarkers of Alzheimer's Disease: Current Evidence and Future Perspectives. Brain Sci 11 (2). doi:https://doi.org/10.3390/brainsci11020215

  93. Gao J, Wang L, Gao C, Arakawa H, Perry G (1866) Wang X (2020) TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP transgenic mouse model for Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 1:165580. https://doi.org/10.1016/j.bbadis.2019.165580

    Article  CAS  Google Scholar 

  94. Flanagan EP, Duffy JR, Whitwell JL, Vemuri P, Dickson DW, Josephs KA (2016) Mixed tau and TDP-43 pathology in a patient with unclassifiable primary progressive aphasia. Neurocase 22(1):55–59. https://doi.org/10.1080/13554794.2015.1041534

    Article  PubMed  Google Scholar 

  95. Josephs KA, Dickson DW (2016) TDP-43 in the olfactory bulb in Alzheimer’s disease. Neuropathol Appl Neurobiol 42(4):390–393. https://doi.org/10.1111/nan.12309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA (2016) TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain 139(11):2983–2993. https://doi.org/10.1093/brain/aww224

    Article  PubMed  PubMed Central  Google Scholar 

  97. Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, Liesinger AM, Petersen RC et al (2016) Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 131(4):571–585. https://doi.org/10.1007/s00401-016-1537-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Aoki N, Murray ME, Ogaki K, Fujioka S, Rutherford NJ, Rademakers R, Ross OA, Dickson DW (2015) Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A. Acta Neuropathol 129(1):53–64. https://doi.org/10.1007/s00401-014-1358-z

    Article  CAS  PubMed  Google Scholar 

  99. Buciuc M, Wennberg AM, Weigand SD, Murray ME, Senjem ML, Spychalla AJ, Boeve BF, Knopman DS et al (2020) Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes. J Alzheimers Dis 73(4):1511–1523. https://doi.org/10.3233/jad-191040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Smith VD, Bachstetter AD, Ighodaro E, Roberts K, Abner EL, Fardo DW, Nelson PT (2018) Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi. Brain Pathol 28(2):264–273. https://doi.org/10.1111/bpa.12505

    Article  CAS  PubMed  Google Scholar 

  101. Nag S, Yu L, Capuano AW, Wilson RS, Leurgans SE, Bennett DA, Schneider JA (2015) Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease. Ann Neurol 77(6):942–952. https://doi.org/10.1002/ana.24388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vanden Broeck L, Kleinberger G, Chapuis J, Gistelinck M, Amouyel P, Van Broeckhoven C, Lambert JC, Callaerts P et al (2015) Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism. Neurobiol Aging 36(2):1121–1129. https://doi.org/10.1016/j.neurobiolaging.2014.09.001

    Article  CAS  PubMed  Google Scholar 

  103. Miklossy J, Steele JC, Yu S, McCall S, Sandberg G, McGeer EG, McGeer PL (2008) Enduring involvement of tau, beta-amyloid, alpha-synuclein, ubiquitin and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS/PDC). Acta Neuropathol 116(6):625–637. https://doi.org/10.1007/s00401-008-0439-2

    Article  CAS  PubMed  Google Scholar 

  104. Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T, Yamazaki M, Oyanagi K (2007) TDP-43 is deposited in the Guam parkinsonism-dementia brains. Brain 130(Pt 5):1386–1394. https://doi.org/10.1093/brain/awm065

    Article  PubMed  Google Scholar 

  105. Geser F, Winton MJ, Kwong LK, Xu Y, Xie SX, Igaz LM, Garruto RM, Perl DP et al (2008) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115(1):133–145. https://doi.org/10.1007/s00401-007-0257-y

    Article  CAS  PubMed  Google Scholar 

  106. Oyanagi K, Yamazaki M, Hashimoto T, Asakawa M, Wakabayashi K, Takahashi H (2015) Hippocampal sclerosis in the parkinsonism-dementia complex of Guam: quantitative examination of neurons, neurofibrillary tangles, and TDP-43 immunoreactivity in CA1. Neuropathology 35(3):224–235. https://doi.org/10.1111/neup.12185

    Article  CAS  PubMed  Google Scholar 

  107. Farrer MJ, Hulihan MM, Kachergus JM, Dächsel JC, Stoessl AJ, Grantier LL, Calne S, Calne DB et al (2009) DCTN1 mutations in Perry syndrome. Nat Genet 41(2):163–165. https://doi.org/10.1038/ng.293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mishima T, Deshimaru M, Watanabe T, Kubota K, Kinoshita-Kawada M, Yuasa-Kawada J, Takasaki K, Uehara Y et al (2018) Behavioral defects in a DCTN1(G71A) transgenic mouse model of Perry syndrome. Neurosci Lett 666:98–103. https://doi.org/10.1016/j.neulet.2017.12.038

    Article  CAS  PubMed  Google Scholar 

  109. Wider C, Wszolek ZK (2008) Rapidly progressive familial parkinsonism with central hypoventilation, depression and weight loss (Perry syndrome)–a literature review. Parkinsonism Relat Disord 14(1):1–7. https://doi.org/10.1016/j.parkreldis.2007.07.014

    Article  PubMed  Google Scholar 

  110. Mishima T, Koga S, Lin WL, Kasanuki K, Castanedes-Casey M, Wszolek ZK, Oh SJ, Tsuboi Y et al (2017) Perry Syndrome: A Distinctive Type of TDP-43 Proteinopathy. J Neuropathol Exp Neurol 76(8):676–682. https://doi.org/10.1093/jnen/nlx049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wider C, Dickson DW, Stoessl AJ, Tsuboi Y, Chapon F, Gutmann L, Lechevalier B, Calne DB et al (2009) Pallidonigral TDP-43 pathology in Perry syndrome. Parkinsonism Relat Disord 15(4):281–286. https://doi.org/10.1016/j.parkreldis.2008.07.005

    Article  PubMed  Google Scholar 

  112. Mishima T, Fujioka S, Tomiyama H, Yabe I, Kurisaki R, Fujii N, Neshige R, Ross OA et al (2018) Establishing diagnostic criteria for Perry syndrome. J Neurol Neurosurg Psychiatry 89(5):482–487. https://doi.org/10.1136/jnnp-2017-316864

    Article  PubMed  Google Scholar 

  113. Hosaka Y, Inoshita T, Shiba-Fukushima K, Cui C, Arano T, Imai Y, Hattori N (2017) Reduced TDP-43 Expression Improves Neuronal Activities in a Drosophila Model of Perry Syndrome. EBioMedicine 21:218–227. https://doi.org/10.1016/j.ebiom.2017.06.002

    Article  PubMed  PubMed Central  Google Scholar 

  114. Wider C, Dachsel JC, Farrer MJ, Dickson DW, Tsuboi Y, Wszolek ZK (2010) Elucidating the genetics and pathology of Perry syndrome. J Neurol Sci 289(1–2):149–154. https://doi.org/10.1016/j.jns.2009.08.044

    Article  PubMed  Google Scholar 

  115. Deshimaru M, Kinoshita-Kawada M, Kubota K, Watanabe T, Tanaka Y, Hirano S, Ishidate F, Hiramoto M, et al (2021) DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation. Int J Mol Sci 22 (8). doi:https://doi.org/10.3390/ijms22083985

  116. St-Amour I, Turgeon A, Goupil C, Planel E, Hébert SS (2018) Co-occurrence of mixed proteinopathies in late-stage Huntington’s disease. Acta Neuropathol 135(2):249–265. https://doi.org/10.1007/s00401-017-1786-7

    Article  CAS  PubMed  Google Scholar 

  117. Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL (2008) Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J Neuropathol Exp Neurol 67(12):1159–1165. https://doi.org/10.1097/NEN.0b013e31818e8951

    Article  PubMed  Google Scholar 

  118. Kovacs GG, Murrell JR, Horvath S, Haraszti L, Majtenyi K, Molnar MJ, Budka H, Ghetti B et al (2009) TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov Disord 24(12):1843–1847. https://doi.org/10.1002/mds.22697

    Article  PubMed  Google Scholar 

  119. Coudert L, Nonaka T, Bernard E, Hasegawa M, Schaeffer L, Leblanc P (2019) Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models. Cell Mol Life Sci 76(13):2615–2632. https://doi.org/10.1007/s00018-019-03059-8

    Article  CAS  PubMed  Google Scholar 

  120. Tauffenberger A, Chitramuthu BP, Bateman A, Bennett HP, Parker JA (2013) Reduction of polyglutamine toxicity by TDP-43, FUS and progranulin in Huntington’s disease models. Hum Mol Genet 22(4):782–794. https://doi.org/10.1093/hmg/dds485

    Article  CAS  PubMed  Google Scholar 

  121. Zhang L, Chen Y, Liu M, Wang Y, Peng G (2019) TDP-43 and Limbic-Predominant Age-Related TDP-43 Encephalopathy. Front Aging Neurosci 11:376. https://doi.org/10.3389/fnagi.2019.00376

    Article  CAS  PubMed  Google Scholar 

  122. Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I et al (2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 142(6):1503–1527. https://doi.org/10.1093/brain/awz099

    Article  PubMed  PubMed Central  Google Scholar 

  123. Cho SH, Choi SM, Kim BC, Song WY, Kim HS, Lee KH (2020) An Autopsy-Proven Case of Limbic-Predominant Age-Related TDP-43 Encephalopathy. Yonsei Med J 61(8):731–735. https://doi.org/10.3349/ymj.2020.61.8.731

    Article  PubMed  PubMed Central  Google Scholar 

  124. Jo M, Lee S, Jeon YM, Kim S, Kwon Y, Kim HJ (2020) The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med. https://doi.org/10.1038/s12276-020-00513-7

    Article  PubMed  PubMed Central  Google Scholar 

  125. Nag S, Yu L, Wilson RS, Chen EY, Bennett DA, Schneider JA (2017) TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD. Neurology 88(7):653–660. https://doi.org/10.1212/wnl.0000000000003610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Görß D, Kilimann I, Dyrba M, Nitsch S, Krause B, Teipel S (2020) LATE: not every dementia is Alzheimer’s disease-Discussion of a new disease entity based on a case example : Current status of limbic-predominant age-related TDP-43 encephalopathy (LATE). Nervenarzt. https://doi.org/10.1007/s00115-020-00922-z

    Article  PubMed Central  Google Scholar 

  127. Agrawal S, Yu L, Nag S, Arfanakis K, Barnes LL, Bennett DA, Schneider JA (2021) The association of Lewy bodies with limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes and their role in cognition and Alzheimer’s dementia in older persons. Acta Neuropathol Commun 9(1):156. https://doi.org/10.1186/s40478-021-01260-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Robinson JL, Porta S, Garrett FG, Zhang P, Xie SX, Suh E, Van Deerlin VM, Abner EL et al (2020) Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration. Brain 143(9):2844–2857. https://doi.org/10.1093/brain/awaa219

    Article  PubMed  PubMed Central  Google Scholar 

  129. Nag S, Barnes LL, Yu L, Wilson RS, Bennett DA, Schneider JA (2020) Limbic-predominant age-related TDP-43 encephalopathy in black and white decedents. Neurology. https://doi.org/10.1212/wnl.0000000000010602

    Article  PubMed  PubMed Central  Google Scholar 

  130. Yang HS, Yu L, White CC, Chibnik LB, Chhatwal JP, Sperling RA, Bennett DA, Schneider JA et al (2018) Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study. Lancet Neurol 17(9):773–781. https://doi.org/10.1016/s1474-4422(18)30251-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Nelson PT, Gal Z, Wang WX, Niedowicz DM, Artiushin SC, Wycoff S, Wei A, Jicha GA et al (2019) TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels. Neurobiol Dis 125:67–76. https://doi.org/10.1016/j.nbd.2019.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cykowski MD, Powell SZ, Schulz PE, Takei H, Rivera AL, Jackson RE, Roman G, Jicha GA et al (2017) Hippocampal Sclerosis in Older Patients: Practical Examples and Guidance With a Focus on Cerebral Age-Related TDP-43 With Sclerosis. Arch Pathol Lab Med 141(8):1113–1126. https://doi.org/10.5858/arpa.2016-0469-SA

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Vanier MT (2010) Niemann-Pick disease type C. Orphanet J Rare Dis 5:16. https://doi.org/10.1186/1750-1172-5-16

    Article  PubMed  PubMed Central  Google Scholar 

  134. Dardis A, Zampieri S, Canterini S, Newell KL, Stuani C, Murrell JR, Ghetti B, Fiorenza MT et al (2016) Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C. Acta Neuropathol Commun 4(1):52. https://doi.org/10.1186/s40478-016-0325-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sosunov A, Olabarria M, Goldman JE (2018) Alexander disease: an astrocytopathy that produces a leukodystrophy. Brain Pathol 28(3):388–398. https://doi.org/10.1111/bpa.12601

    Article  PubMed  PubMed Central  Google Scholar 

  136. Walker AK, Daniels CM, Goldman JE, Trojanowski JQ, Lee VM, Messing A (2014) Astrocytic TDP-43 pathology in Alexander disease. J Neurosci 34(19):6448–6458. https://doi.org/10.1523/jneurosci.0248-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jany PL, Hagemann TL, Messing A (2013) GFAP expression as an indicator of disease severity in mouse models of Alexander disease. ASN Neuro 5(1):e00109. https://doi.org/10.1042/an20130003

    Article  PubMed  PubMed Central  Google Scholar 

  138. Tao J, Wu H, Lin Q, Wei W, Lu XH, Cantle JP, Ao Y, Olsen RW et al (2011) Deletion of astroglial Dicer causes non-cell-autonomous neuronal dysfunction and degeneration. J Neurosci 31(22):8306–8319. https://doi.org/10.1523/jneurosci.0567-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Rayaprolu S, Fujioka S, Traynor S, Soto-Ortolaza AI, Petrucelli L, Dickson DW, Rademakers R, Boylan KB et al (2013) TARDBP mutations in Parkinson’s disease. Parkinsonism Relat Disord 19(3):312–315. https://doi.org/10.1016/j.parkreldis.2012.11.003

    Article  PubMed  Google Scholar 

  140. Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114(3):221–229. https://doi.org/10.1007/s00401-007-0261-2

    Article  CAS  PubMed  Google Scholar 

  141. Kokoulina P, Rohn TT (2010) Caspase-cleaved transactivation response DNA-binding protein 43 in Parkinson’s disease and dementia with Lewy bodies. Neurodegener Dis 7(4):243–250. https://doi.org/10.1159/000287952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yokota O, Davidson Y, Arai T, Hasegawa M, Akiyama H, Ishizu H, Terada S, Sikkink S et al (2010) Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease. Acta Neuropathol 120(6):789–801. https://doi.org/10.1007/s00401-010-0731-9

    Article  CAS  PubMed  Google Scholar 

  143. Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O et al (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294. https://doi.org/10.1016/j.brainres.2007.09.048

    Article  CAS  PubMed  Google Scholar 

  144. McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J (2017) TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies and ageing. Brain Pathol 27(4):472–479. https://doi.org/10.1111/bpa.12424

    Article  CAS  PubMed  Google Scholar 

  145. Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, Iritani S, Onaya M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117(2):125–136. https://doi.org/10.1007/s00401-008-0480-1

    Article  CAS  PubMed  Google Scholar 

  146. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305(5688):1292–1295. https://doi.org/10.1126/science.1101738

    Article  CAS  PubMed  Google Scholar 

  147. Dehay B, Bové J, Rodríguez-Muela N, Perier C, Recasens A, Boya P, Vila M (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 30(37):12535–12544. https://doi.org/10.1523/jneurosci.1920-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44(3):415–422. https://doi.org/10.1002/ana.410440324

    Article  CAS  PubMed  Google Scholar 

  149. Koga S, Lin WL, Walton RL, Ross OA, Dickson DW (2018) TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions. Neuropathol Appl Neurobiol 44(7):707–721. https://doi.org/10.1111/nan.12485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Geser F, Malunda JA, Hurtig HI, Duda JE, Wenning GK, Gilman S, Low PA, Lee VM et al (2011) TDP-43 pathology occurs infrequently in multiple system atrophy. Neuropathol Appl Neurobiol 37(4):358–365. https://doi.org/10.1111/j.1365-2990.2010.01136.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Koga S, Sanchez-Contreras M, Josephs KA, Uitti RJ, Graff-Radford N, van Gerpen JA, Cheshire WP, Wszolek ZK et al (2017) Distribution and characteristics of transactive response DNA binding protein 43 kDa pathology in progressive supranuclear palsy. Mov Disord 32(2):246–255. https://doi.org/10.1002/mds.26809

    Article  CAS  PubMed  Google Scholar 

  152. Yokota O, Davidson Y, Bigio EH, Ishizu H, Terada S, Arai T, Hasegawa M, Akiyama H et al (2010) Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy. Acta Neuropathol 120(1):55–66. https://doi.org/10.1007/s00401-010-0702-1

    Article  PubMed  PubMed Central  Google Scholar 

  153. Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67(6):555–564. https://doi.org/10.1097/NEN.0b013e31817713b5

    Article  CAS  PubMed  Google Scholar 

  154. Koga S, Kouri N, Walton RL, Ebbert MTW, Josephs KA, Litvan I, Graff-Radford N, Ahlskog JE et al (2018) Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype. Acta Neuropathol 136(3):389–404. https://doi.org/10.1007/s00401-018-1878-z

    Article  PubMed  PubMed Central  Google Scholar 

  155. Kouri N, Oshima K, Takahashi M, Murray ME, Ahmed Z, Parisi JE, Yen SH, Dickson DW (2013) Corticobasal degeneration with olivopontocerebellar atrophy and TDP-43 pathology: an unusual clinicopathologic variant of CBD. Acta Neuropathol 125(5):741–752. https://doi.org/10.1007/s00401-013-1087-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Chen HJ, Mitchell JC, Novoselov S, Miller J, Nishimura AL, Scotter EL, Vance CA, Cheetham ME et al (2016) The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis. Brain 139(Pt 5):1417–1432. https://doi.org/10.1093/brain/aww028

    Article  PubMed  PubMed Central  Google Scholar 

  157. Tefera TW, Steyn FJ, Ngo ST, Borges K (2021) CNS glucose metabolism in Amyotrophic Lateral Sclerosis: a therapeutic target? Cell Biosci 11(1):14. https://doi.org/10.1186/s13578-020-00511-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Rojas-Prats E, Martinez-Gonzalez L, Gonzalo-Consuegra C, Liachko NF, Perez C, Ramírez D, Kraemer BC, Martin-Requero Á, et al (2020) Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis. Eur J Med Chem:112968. doi:https://doi.org/10.1016/j.ejmech.2020.112968

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This work was supported by grants from the Natural Science Foundation of Hebei Province (H2019406165).

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  1. Yan-Zhe Liao and Jing Ma contributed equally to this paper.

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  1. Department of Neurology, School of Medicine, Chengde Medical University Affiliated Hospital, Chengde Medical University, Anyuan Road, Chengde, People’s Republic of China

    Yan-Zhe Liao

  2. Department of Neurology, Chengde Medical University Affiliated Hospital, Chengde Medical University, No.36 Nanyingzi Road, Chengde, People’s Republic of China

    Jing Ma & Jie-Zhi Dou

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  1. Yan-Zhe Liao
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YZL, JM and JZD did the manuscript preparation and drafting. JM and JZD are responsible for the study conception and design. YZL wrote the first draft of the manuscript. All authors have contributed to the manuscript revising and editing critically for important intellectual content and given final approval of the version and agreed to be accountable for all aspects of the work presented here.

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Liao, YZ., Ma, J. & Dou, JZ. The Role of TDP-43 in Neurodegenerative Disease. Mol Neurobiol 59, 4223–4241 (2022). https://doi.org/10.1007/s12035-022-02847-x

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