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TDP-43 proteinopathy

MedGen UID:
439336
•Concept ID:
C2718017
•
Disease or Syndrome
Synonyms: Proteinopathies, TDP-43; Proteinopathy, TDP-43; TDP 43 Proteinopathies; TDP-43 Proteinopathies; TDP-43 Proteinopathy
 
Monarch Initiative: MONDO:0700038

Definition

Disease characterized by the presence of abnormally phosphorylated, ubiquitinated, and cleaved DNA-binding protein TDP-43 in affected brain and spinal cord. Inclusions of the pathologic protein in neurons and glia, without the presence of AMYLOID, is the major feature of these conditions, thus making these proteinopathies distinct from most other neurogenerative disorders in which protein misfolding leads to brain amyloidosis. Both frontotemporal lobar degeneration and AMYOTROPHIC LATERAL SCLEROSIS exhibit this common method of pathogenesis and thus they may represent two extremes of a continuous clinicopathological spectrum of one disease. [from MONDO]

Professional guidelines

PubMed

Stathmin 2 is a potential treatment target for TDP-43 proteinopathy in amyotrophic lateral sclerosis.
Liu Y, Yan D, Yang L, Chen X, Hu C, Chen M
Transl Neurodegener 2024 Apr 11;13(1):20. doi: 10.1186/s40035-024-00413-0. PMID: 38600555Free PMC Article
Differential diagnosis of amyotrophic lateral sclerosis from Guillain-Barré syndrome by quantitative determination of TDP-43 in cerebrospinal fluid.
Hosokawa M, Arai T, Yamashita M, Tsuji H, Nonaka T, Masuda-Suzukake M, Tamaoka A, Hasegawa M, Akiyama H
Int J Neurosci 2014 May;124(5):344-9. Epub 2013 Oct 31 doi: 10.3109/00207454.2013.848440. PMID: 24066851
Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration.
Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL 3rd, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM; Consortium for Frontotemporal Lobar Degeneration
Acta Neuropathol 2007 Jul;114(1):5-22. Epub 2007 Jun 20 doi: 10.1007/s00401-007-0237-2. PMID: 17579875Free PMC Article

Recent clinical studies

Etiology

Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology.
Ziff OJ, Neeves J, Mitchell J, Tyzack G, Martinez-Ruiz C, Luisier R, Chakrabarti AM, McGranahan N, Litchfield K, Boulton SJ, Al-Chalabi A, Kelly G, Humphrey J, Patani R
Nat Commun 2023 Apr 20;14(1):2176. doi: 10.1038/s41467-023-37630-6. PMID: 37080969Free PMC Article
TDP-43 Proteinopathy and Tauopathy: Do They Have Pathomechanistic Links?
Riku Y, Yoshida M, Iwasaki Y, Sobue G, Katsuno M, Ishigaki S
Int J Mol Sci 2022 Dec 12;23(24) doi: 10.3390/ijms232415755. PMID: 36555399Free PMC Article
Update on genetics of amyotrophic lateral sclerosis.
Brenner D, Freischmidt A
Curr Opin Neurol 2022 Oct 1;35(5):672-677. Epub 2022 Aug 8 doi: 10.1097/WCO.0000000000001093. PMID: 35942673
Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.
Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I, Attems J, Brayne C, Coyle-Gilchrist ITS, Chui HC, Fardo DW, Flanagan ME, Halliday G, Hokkanen SRK, Hunter S, Jicha GA, Katsumata Y, Kawas CH, Keene CD, Kovacs GG, Kukull WA, Levey AI, Makkinejad N, Montine TJ, Murayama S, Murray ME, Nag S, Rissman RA, Seeley WW, Sperling RA, White CL 3rd, Yu L, Schneider JA
Brain 2019 Jun 1;142(6):1503-1527. doi: 10.1093/brain/awz099. PMID: 31039256Free PMC Article
Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.
Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G, Pulst SM, Taylor JP, Rigo F, Gitler AD
Nature 2017 Apr 20;544(7650):367-371. Epub 2017 Apr 12 doi: 10.1038/nature22038. PMID: 28405022Free PMC Article

Diagnosis

Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.
Agra Almeida Quadros AR, Li Z, Wang X, Ndayambaje IS, Aryal S, Ramesh N, Nolan M, Jayakumar R, Han Y, Stillman H, Aguilar C, Wheeler HJ, Connors T, Lopez-Erauskin J, Baughn MW, Melamed Z, Beccari MS, Olmedo Martínez L, Canori M, Lee CZ, Moran L, Draper I, Kopin AS, Oakley DH, Dickson DW, Cleveland DW, Hyman BT, Das S, Ertekin-Taner N, Lagier-Tourenne C
Acta Neuropathol 2024 Jan 4;147(1):9. doi: 10.1007/s00401-023-02655-0. PMID: 38175301Free PMC Article
TDP-43 Proteinopathy Specific Biomarker Development.
Cordts I, Wachinger A, Scialo C, Lingor P, Polymenidou M, Buratti E, Feneberg E
Cells 2023 Feb 12;12(4) doi: 10.3390/cells12040597. PMID: 36831264Free PMC Article
Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43.
Tarutani A, Adachi T, Akatsu H, Hashizume Y, Hasegawa K, Saito Y, Robinson AC, Mann DMA, Yoshida M, Murayama S, Hasegawa M
Acta Neuropathol 2022 Jun;143(6):613-640. Epub 2022 May 5 doi: 10.1007/s00401-022-02426-3. PMID: 35513543Free PMC Article
Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.
Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I, Attems J, Brayne C, Coyle-Gilchrist ITS, Chui HC, Fardo DW, Flanagan ME, Halliday G, Hokkanen SRK, Hunter S, Jicha GA, Katsumata Y, Kawas CH, Keene CD, Kovacs GG, Kukull WA, Levey AI, Makkinejad N, Montine TJ, Murayama S, Murray ME, Nag S, Rissman RA, Seeley WW, Sperling RA, White CL 3rd, Yu L, Schneider JA
Brain 2019 Jun 1;142(6):1503-1527. doi: 10.1093/brain/awz099. PMID: 31039256Free PMC Article
Significance and limitation of the pathological classification of TDP-43 proteinopathy.
Arai T
Neuropathology 2014 Dec;34(6):578-88. Epub 2014 Sep 8 doi: 10.1111/neup.12138. PMID: 25196969

Therapy

Relation of Motor Impairments to Neuropathologic Changes of Limbic-Predominant Age-Related TDP-43 Encephalopathy in Older Adults.
Oveisgharan S, Yu L, Agrawal S, Nag S, Bennett DA, Buchman AS, Schneider JA
Neurology 2023 Oct 10;101(15):e1542-e1553. Epub 2023 Aug 21 doi: 10.1212/WNL.0000000000207726. PMID: 37604667Free PMC Article
White matter damage due to vascular, tau, and TDP-43 pathologies and its relevance to cognition.
Raghavan S, Przybelski SA, Reid RI, Lesnick TG, Ramanan VK, Botha H, Matchett BJ, Murray ME, Reichard RR, Knopman DS, Graff-Radford J, Jones DT, Lowe VJ, Mielke MM, Machulda MM, Petersen RC, Kantarci K, Whitwell JL, Josephs KA, Jack CR Jr, Vemuri P
Acta Neuropathol Commun 2022 Feb 5;10(1):16. doi: 10.1186/s40478-022-01319-6. PMID: 35123591Free PMC Article
Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy.
Matsukawa K, Kukharsky MS, Park SK, Park S, Watanabe N, Iwatsubo T, Hashimoto T, Liebman SW, Shelkovnikova TA
RNA Biol 2021 Nov;18(11):1546-1554. Epub 2021 Jan 11 doi: 10.1080/15476286.2020.1860580. PMID: 33427561Free PMC Article
Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.
Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G, Pulst SM, Taylor JP, Rigo F, Gitler AD
Nature 2017 Apr 20;544(7650):367-371. Epub 2017 Apr 12 doi: 10.1038/nature22038. PMID: 28405022Free PMC Article
Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model.
LaClair KD, Donde A, Ling JP, Jeong YH, Chhabra R, Martin LJ, Wong PC
Acta Neuropathol 2016 Dec;132(6):859-873. Epub 2016 Oct 26 doi: 10.1007/s00401-016-1637-y. PMID: 27785573Free PMC Article

Prognosis

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.
Seddighi S, Qi YA, Brown AL, Wilkins OG, Bereda C, Belair C, Zhang YJ, Prudencio M, Keuss MJ, Khandeshi A, Pickles S, Kargbo-Hill SE, Hawrot J, Ramos DM, Yuan H, Roberts J, Sacramento EK, Shah SI, Nalls MA, Colón-Mercado JM, Reyes JF, Ryan VH, Nelson MP, Cook CN, Li Z, Screven L, Kwan JY, Mehta PR, Zanovello M, Hallegger M, Shantaraman A, Ping L, Koike Y, Oskarsson B, Staff NP, Duong DM, Ahmed A, Secrier M, Ule J, Jacobson S, Reich DS, Rohrer JD, Malaspina A, Dickson DW, Glass JD, Ori A, Seyfried NT, Maragkakis M, Petrucelli L, Fratta P, Ward ME
Sci Transl Med 2024 Feb 14;16(734):eadg7162. doi: 10.1126/scitranslmed.adg7162. PMID: 38277467
Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy.
Katsumata Y, Abner EL, Karanth S, Teylan MA, Mock CN, Cykowski MD, Lee EB, Boehme KL, Mukherjee S, Kauwe JSK, Kryscio RJ, Schmitt FA, Fardo DW, Nelson PT
Acta Neuropathol 2020 Nov;140(5):659-674. Epub 2020 Aug 14 doi: 10.1007/s00401-020-02211-0. PMID: 32797255Free PMC Article
Utility of FDG-PET in diagnosis of Alzheimer-related TDP-43 proteinopathy.
Buciuc M, Botha H, Murray ME, Schwarz CG, Senjem ML, Jones DT, Knopman DS, Boeve BF, Petersen RC, Jack CR Jr, Petrucelli L, Parisi JE, Dickson DW, Lowe V, Whitwell JL, Josephs KA
Neurology 2020 Jul 7;95(1):e23-e34. Epub 2020 Jun 9 doi: 10.1212/WNL.0000000000009722. PMID: 32518145Free PMC Article
RRM adjacent TARDBP mutations disrupt RNA binding and enhance TDP-43 proteinopathy.
Chen HJ, Topp SD, Hui HS, Zacco E, Katarya M, McLoughlin C, King A, Smith BN, Troakes C, Pastore A, Shaw CE
Brain 2019 Dec 1;142(12):3753-3770. doi: 10.1093/brain/awz313. PMID: 31605140Free PMC Article
TDP-43 proteinopathy in Theiler's murine encephalomyelitis virus infection.
Masaki K, Sonobe Y, Ghadge G, Pytel P, Roos RP
PLoS Pathog 2019 Feb;15(2):e1007574. Epub 2019 Feb 11 doi: 10.1371/journal.ppat.1007574. PMID: 30742696Free PMC Article

Clinical prediction guides

Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns.
Pérez-Berlanga M, Wiersma VI, Zbinden A, De Vos L, Wagner U, Foglieni C, Mallona I, Betz KM, Cléry A, Weber J, Guo Z, Rigort R, de Rossi P, Manglunia R, Tantardini E, Sahadevan S, Stach O, Hruska-Plochan M, Allain FH, Paganetti P, Polymenidou M
EMBO J 2023 Sep 4;42(17):e111719. Epub 2023 Jul 11 doi: 10.15252/embj.2022111719. PMID: 37431963Free PMC Article
C-terminal frameshift variant of TDP-43 with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD.
Ervilha Pereira P, Schuermans N, Meylemans A, LeBlanc P, Versluys L, Copley KE, Rubien JD, Altheimer C, Peetermans M, Debackere E, Vanakker O, Janssens S, Baets J, Verhoeven K, Lammens M, Symoens S, De Paepe B, Barmada SJ, Shorter J, De Bleecker JL, Bogaert E, Dermaut B
Acta Neuropathol 2023 Jun;145(6):793-814. Epub 2023 Mar 31 doi: 10.1007/s00401-023-02565-1. PMID: 37000196Free PMC Article
TDP-43 Proteinopathy and Tauopathy: Do They Have Pathomechanistic Links?
Riku Y, Yoshida M, Iwasaki Y, Sobue G, Katsuno M, Ishigaki S
Int J Mol Sci 2022 Dec 12;23(24) doi: 10.3390/ijms232415755. PMID: 36555399Free PMC Article
Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.
Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I, Attems J, Brayne C, Coyle-Gilchrist ITS, Chui HC, Fardo DW, Flanagan ME, Halliday G, Hokkanen SRK, Hunter S, Jicha GA, Katsumata Y, Kawas CH, Keene CD, Kovacs GG, Kukull WA, Levey AI, Makkinejad N, Montine TJ, Murayama S, Murray ME, Nag S, Rissman RA, Seeley WW, Sperling RA, White CL 3rd, Yu L, Schneider JA
Brain 2019 Jun 1;142(6):1503-1527. doi: 10.1093/brain/awz099. PMID: 31039256Free PMC Article
RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43.
Mann JR, Gleixner AM, Mauna JC, Gomes E, DeChellis-Marks MR, Needham PG, Copley KE, Hurtle B, Portz B, Pyles NJ, Guo L, Calder CB, Wills ZP, Pandey UB, Kofler JK, Brodsky JL, Thathiah A, Shorter J, Donnelly CJ
Neuron 2019 Apr 17;102(2):321-338.e8. Epub 2019 Feb 27 doi: 10.1016/j.neuron.2019.01.048. PMID: 30826182Free PMC Article

Recent systematic reviews

Prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults: systematic review and meta-analysis.
Nascimento C, Di Lorenzo Alho AT, Bazan Conceição Amaral C, Leite REP, Nitrini R, Jacob-Filho W, Pasqualucci CA, Hokkanen SRK, Hunter S, Keage H, Kovacs GG, Grinberg LT, Suemoto CK
Neuropathol Appl Neurobiol 2018 Apr;44(3):286-297. Epub 2017 Sep 20 doi: 10.1111/nan.12430. PMID: 28793370Free PMC Article

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