Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.
ALS
FTD
Immunotherapy
Neuropathology
Pathomechanism
Spreading
TDP-43
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
03 Oct 2024
03 Oct 2024
Historique:
received:
30
04
2024
accepted:
23
09
2024
medline:
4
10
2024
pubmed:
4
10
2024
entrez:
4
10
2024
Statut:
epublish
Résumé
Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.
Identifiants
pubmed: 39363348
doi: 10.1186/s40478-024-01867-z
pii: 10.1186/s40478-024-01867-z
doi:
Substances chimiques
DNA-Binding Proteins
0
Antibodies, Monoclonal
0
TARDBP protein, human
0
Tardbp protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
156Informations de copyright
© 2024. The Author(s).
Références
Afroz T, Chevalier E, Audrain M, Dumayne C, Ziehm T, Moser R et al (2023) Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD. Neurobiol Dis 179:106050. https://doi.org/10.1016/j.nbd.2023.106050
doi: 10.1016/j.nbd.2023.106050
pubmed: 36809847
Afroz T, Perez-Berlanga M, Polymenidou M (2019) Structural transition, function and dysfunction of TDP-43 in neurodegenerative diseases. Chimia (Aarau) 73:380–390. https://doi.org/10.2533/chimia.2019.380
doi: 10.2533/chimia.2019.380
pubmed: 31118120
Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611. https://doi.org/10.1016/j.bbrc.2006.10.093
doi: 10.1016/j.bbrc.2006.10.093
pubmed: 17084815
Arseni D, Chen R, Murzin AG, Peak-Chew SY, Garringer HJ, Newell KL et al (2023) TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Nature 620:898–903. https://doi.org/10.1038/s41586-023-06405-w
doi: 10.1038/s41586-023-06405-w
pubmed: 37532939
Arseni D, Hasegawa M, Murzin AG, Kametani F, Arai M, Yoshida M et al (2021) Structure of pathological TDP-43 filaments from ALS with FTLD. Nature. https://doi.org/10.1038/s41586-021-04199-3
doi: 10.1038/s41586-021-04199-3
pubmed: 34880495
Audrain M, Egesipe AL, Tentillier N, Font L, Ratnam M, Mottier L et al (2023) Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF. Brain Commun 5:fcad306. https://doi.org/10.1093/braincomms/fcad306
doi: 10.1093/braincomms/fcad306
pubmed: 38025276
Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M et al (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74:20–38. https://doi.org/10.1002/ana.23937
doi: 10.1002/ana.23937
pubmed: 23686809
Buratti E (2018) TDP-43 post-translational modifications in health and disease. Expert Opin Ther Targets 22:279–293. https://doi.org/10.1080/14728222.2018.1439923
doi: 10.1080/14728222.2018.1439923
pubmed: 29431050
Chornenkyy Y, Fardo DW, Nelson PT (2019) Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy. Lab Invest 99:993–1007. https://doi.org/10.1038/s41374-019-0196-y
doi: 10.1038/s41374-019-0196-y
pubmed: 30742063
Cohen TJ, Hwang AW, Restrepo CR, Yuan CX, Trojanowski JQ, Lee VM (2015) An acetylation switch controls TDP-43 function and aggregation propensity. Nat Commun 6:5845. https://doi.org/10.1038/ncomms6845
doi: 10.1038/ncomms6845
pubmed: 25556531
Conicella AE, Zerze GH, Mittal J, Fawzi NL (2016) ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24:1537–1549. https://doi.org/10.1016/j.str.2016.07.007
doi: 10.1016/j.str.2016.07.007
pubmed: 27545621
Ding X, Ma M, Teng J, Teng RK, Zhou S, Yin J et al (2015) Exposure to ALS-FTD-CSF generates TDP-43 aggregates in glioblastoma cells through exosomes and TNTs-like structure. Oncotarget 6:24178–24191. https://doi.org/10.18632/oncotarget.4680
doi: 10.18632/oncotarget.4680
pubmed: 26172304
Gasset-Rosa F, Lu S, Yu H, Chen C, Melamed Z, Guo L et al (2019) Cytoplasmic TDP-43 de-mixing independent of stress granules drives inhibition of nuclear import, loss of nuclear TDP-43, and cell death. Neuron 102(339–357):e337. https://doi.org/10.1016/j.neuron.2019.02.038
doi: 10.1016/j.neuron.2019.02.038
Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T et al (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738. https://doi.org/10.1172/JCI44867
doi: 10.1172/JCI44867
pubmed: 21206091
pmcid: 3026736
Iguchi Y, Eid L, Parent M, Soucy G, Bareil C, Riku Y et al (2016) Exosome secretion is a key pathway for clearance of pathological TDP-43. Brain 139:3187–3201. https://doi.org/10.1093/brain/aww237
doi: 10.1093/brain/aww237
pubmed: 27679482
pmcid: 5840881
Karanth S, Nelson PT, Katsumata Y, Kryscio RJ, Schmitt FA, Fardo DW et al (2020) Prevalence and clinical phenotype of quadruple misfolded proteins in older adults. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2020.1741
doi: 10.1001/jamaneurol.2020.1741
pubmed: 32568358
pmcid: 7309572
Kawakami I, Arai T, Hasegawa M (2019) The basis of clinicopathological heterogeneity in TDP-43 proteinopathy. Acta Neuropathol 138:751–770. https://doi.org/10.1007/s00401-019-02077-x
doi: 10.1007/s00401-019-02077-x
pubmed: 31555895
pmcid: 6800885
Kouhi A, Pachipulusu V, Kapenstein T, Hu P, Epstein AL, Khawli LA (2021) Brain disposition of antibody-based therapeutics: dogma, approaches and perspectives. Int J Mol Sci 22:6442. https://doi.org/10.3390/ijms22126442
doi: 10.3390/ijms22126442
pubmed: 34208575
pmcid: 8235515
Kumar ST, Nazarov S, Porta S, Maharjan N, Cendrowska U, Kabani M et al (2023) Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage. Nat Neurosci 26:983–996. https://doi.org/10.1038/s41593-023-01341-4
doi: 10.1038/s41593-023-01341-4
pubmed: 37248338
pmcid: 10244175
Kwong LK, Irwin DJ, Walker AK, Xu Y, Riddle DM, Trojanowski JQ et al (2014) Novel monoclonal antibodies to normal and pathologically altered human TDP-43 proteins. Acta Neuropathol Commun 2:33. https://doi.org/10.1186/2051-5960-2-33
doi: 10.1186/2051-5960-2-33
pubmed: 24690345
Laferriere F, Maniecka Z, Perez-Berlanga M, Hruska-Plochan M, Gilhespy L, Hock EM et al (2019) TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Nat Neurosci 22:65–77. https://doi.org/10.1038/s41593-018-0294-y
doi: 10.1038/s41593-018-0294-y
pubmed: 30559480
Lee EB, Porta S, Michael Baer G, Xu Y, Suh E, Kwong LK et al (2017) Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134:65–78. https://doi.org/10.1007/s00401-017-1679-9
doi: 10.1007/s00401-017-1679-9
pubmed: 28130640
Maurel C, Chami AA, Thepault RA, Marouillat S, Blasco H, Corcia P et al (2020) A role for SUMOylation in the formation and cellular localization of TDP-43 aggregates in amyotrophic lateral sclerosis. Mol Neurobiol 57:1361–1373. https://doi.org/10.1007/s12035-019-01810-7
doi: 10.1007/s12035-019-01810-7
pubmed: 31728929
McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW et al (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:918–929. https://doi.org/10.1097/NEN.0b013e3181ee7d85
doi: 10.1097/NEN.0b013e3181ee7d85
pubmed: 20720505
Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K et al (2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 142:1503–1527. https://doi.org/10.1093/brain/awz099
doi: 10.1093/brain/awz099
pubmed: 31039256
pmcid: 6536849
Neumann M (2009) Molecular neuropathology of TDP-43 proteinopathies. Int J Mol Sci 10:232–246. https://doi.org/10.3390/ijms10010232
doi: 10.3390/ijms10010232
pubmed: 19333444
Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y et al (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149. https://doi.org/10.1007/s00401-008-0477-9
doi: 10.1007/s00401-008-0477-9
pubmed: 19125255
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108
doi: 10.1126/science.1134108
pubmed: 17023659
Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T et al (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4:124–134. https://doi.org/10.1016/j.celrep.2013.06.007
doi: 10.1016/j.celrep.2013.06.007
pubmed: 23831027
Porta S, Xu Y, Lehr T, Zhang B, Meymand E, Olufemi M et al (2021) Distinct brain-derived TDP-43 strains from FTLD-TDP subtypes induce diverse morphological TDP-43 aggregates and spreading patterns in vitro and in vivo. Neuropathol Appl Neurobiol 47:1033–1049. https://doi.org/10.1111/nan.12732
doi: 10.1111/nan.12732
pubmed: 33971027
Porta S, Xu Y, Restrepo CR, Kwong LK, Zhang B, Brown HJ et al (2018) Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat Commun 9:4220. https://doi.org/10.1038/s41467-018-06548-9
doi: 10.1038/s41467-018-06548-9
pubmed: 30310141
Riemenschneider H, Simonetti F, Sheth U, Katona E, Roth S, Hutten S et al (2023) Targeting the glycine-rich domain of TDP-43 with antibodies prevents its aggregation in vitro and reduces neurofilament levels in vivo. Acta Neuropathol Commun 11:112. https://doi.org/10.1186/s40478-023-01592-z
doi: 10.1186/s40478-023-01592-z
pubmed: 37434215
Salajegheh M, Pinkus JL, Taylor JP, Amato AA, Nazareno R, Baloh RH et al (2009) Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve 40:19–31. https://doi.org/10.1002/mus.21386
doi: 10.1002/mus.21386
pubmed: 19533646
Seyfried NT, Gozal YM, Dammer EB, Xia Q, Duong DM, Cheng D et al (2010) Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. Mol Cell Proteomics 9:705–718. https://doi.org/10.1074/mcp.M800390-MCP200
doi: 10.1074/mcp.M800390-MCP200
pubmed: 20047951
Tamaki Y, Ross JP, Alipour P, Castonguay CE, Li B, Catoire H et al (2023) Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. PLoS Genet 19:e1010606. https://doi.org/10.1371/journal.pgen.1010606
doi: 10.1371/journal.pgen.1010606
pubmed: 36745687
pmcid: 9934440
Tsuji H, Arai T, Kametani F, Nonaka T, Yamashita M, Suzukake M et al (2012) Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain 135:3380–3391. https://doi.org/10.1093/brain/aws230
doi: 10.1093/brain/aws230
pubmed: 23035040
Young AL, Vogel JW, Robinson JL, McMillan CT, Ossenkoppele R, Wolk DA et al (2023) Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies. Brain 146:2975–2988. https://doi.org/10.1093/brain/awad145
doi: 10.1093/brain/awad145
pubmed: 37150879
pmcid: 10317181