TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
10
09
2018
accepted:
14
11
2018
entrez:
19
12
2018
pubmed:
19
12
2018
medline:
22
5
2019
Statut:
ppublish
Résumé
Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathology in affected neurons of people with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Morphological diversity and neuroanatomical distribution of pTDP-43 accumulations allowed classification of FTLD cases into at least four subtypes, which are correlated with clinical presentations and genetic causes. To understand the molecular basis of this heterogeneity, we developed SarkoSpin, a new method for biochemical isolation of pathological TDP-43. By combining SarkoSpin with mass spectrometry, we revealed proteins beyond TDP-43 that become abnormally insoluble in a disease subtype-specific manner. We show that pTDP-43 extracted from brain forms stable assemblies of distinct densities and morphologies that are associated with disease subtypes. Importantly, biochemically extracted pTDP-43 assemblies showed differential neurotoxicity and seeding that were correlated with disease duration of FTLD subjects. Our data are consistent with the notion that disease heterogeneity could originate from alternate pathological TDP-43 conformations, which are reminiscent of prion strains.
Identifiants
pubmed: 30559480
doi: 10.1038/s41593-018-0294-y
pii: 10.1038/s41593-018-0294-y
doi:
Substances chimiques
DNA-Binding Proteins
0
Protein Aggregates
0
TARDBP protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
65-77Commentaires et corrections
Type : CommentIn
Références
Ling, S. C., Polymenidou, M. & Cleveland, D. W. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79, 416–438 (2013).
doi: 10.1016/j.neuron.2013.07.033
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
doi: 10.1126/science.1134108
Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611 (2006).
doi: 10.1016/j.bbrc.2006.10.093
Buratti, E. et al. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 20, 1774–1784 (2001).
doi: 10.1093/emboj/20.7.1774
Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459–468 (2011).
doi: 10.1038/nn.2779
Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452–458 (2011).
doi: 10.1038/nn.2778
Afroz, T. et al. Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat. Commun. 8, 45 (2017).
doi: 10.1038/s41467-017-00062-0
Jiang, L. L. et al. The N-terminal dimerization is required for TDP-43 splicing activity. Sci. Rep. 7, 6196 (2017).
doi: 10.1038/s41598-017-06263-3
Gu, J. et al. Transactive response DNA-binding protein 43 (TDP-43) regulates alternative splicing of tau exon 10: Implications for the pathogenesis of tauopathies. J. Biol. Chem. 292, 10600–10612 (2017).
doi: 10.1074/jbc.M117.783498
Ederle, H. & Dormann, D. TDP-43 and FUS en route from the nucleus to the cytoplasm. FEBS Lett. 591, 1489–1507 (2017).
doi: 10.1002/1873-3468.12646
Dewey, C. M. et al. TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol. Cell. Biol. 31, 1098–1108 (2011).
doi: 10.1128/MCB.01279-10
Alami, N. H. et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81, 536–543 (2014).
doi: 10.1016/j.neuron.2013.12.018
Gopal, P. P., Nirschl, J. J., Klinman, E. & Holzbaur, E. L. Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons. Proc. Natl Acad. Sci. USA 114, E2466–E2475 (2017).
Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).
doi: 10.1016/j.cell.2012.04.017
Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123–133 (2015).
doi: 10.1016/j.cell.2015.09.015
Igaz, L. M. et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am. J. Pathol. 173, 182–194 (2008).
doi: 10.2353/ajpath.2008.080003
Neumann, M. et al. 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 (2009).
doi: 10.1007/s00401-008-0477-9
Lashley, T., Rohrer, J. D., Mead, S. & Revesz, T. Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations. Neuropathol. Appl. Neurobiol. 41, 858–881 (2015).
doi: 10.1111/nan.12250
Neary, D. et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51, 1546–1554 (1998).
doi: 10.1212/WNL.51.6.1546
Mackenzie, I. R. & Neumann, M. Reappraisal of TDP-43 pathology in FTLD-U subtypes. Acta Neuropathol. 134, 79–96 (2017).
doi: 10.1007/s00401-017-1716-8
Lee, E. B. et al. Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol. 134, 65–78 (2017).
doi: 10.1007/s00401-017-1679-9
Nonaka, T. et al. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124–134 (2013).
doi: 10.1016/j.celrep.2013.06.007
Tsuji, H. et al. Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain 135, 3380–3391 (2012).
doi: 10.1093/brain/aws230
Laferrière, F. et al. Quaternary structure of pathological prion protein as a determining factor of strain-specific prion replication dynamics. PLoS Pathog. 9, e1003702 (2013).
doi: 10.1371/journal.ppat.1003702
Polymenidou, M. et al. Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol. 4, 805–814 (2005).
doi: 10.1016/S1474-4422(05)70225-8
Carra, S. et al. Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins. Prog. Neurobiol. 97, 83–100 (2012).
doi: 10.1016/j.pneurobio.2011.09.009
Neumann, M. et al. Absence of heterogeneous nuclear ribonucleoproteins and survival motor neuron protein in TDP-43 positive inclusions in frontotemporal lobar degeneration. Acta Neuropathol. 113, 543–548 (2007).
doi: 10.1007/s00401-007-0221-x
Kametani, F. et al. Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains. Sci. Rep. 6, 23281 (2016).
doi: 10.1038/srep23281
Ingre, C. et al. A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol. Aging 34, 1708.e1–1708.e6 (2013).
doi: 10.1016/j.neurobiolaging.2012.10.009
Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).
doi: 10.1038/nature11280
Zhou, J. et al. Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. Am. J. Hum. Genet. 91, 5–14 (2012).
doi: 10.1016/j.ajhg.2012.05.001
Xu, G., Stevens, S. M. Jr., Moore, B. D., McClung, S. & Borchelt, D. R. Cytosolic proteins lose solubility as amyloid deposits in a transgenic mouse model of Alzheimer-type amyloidosis. Hum. Mol. Genet. 22, 2765–2774 (2013).
doi: 10.1093/hmg/ddt121
McGurk, L. et al. Poly-A binding protein-1 localization to a subset of TDP-43 inclusions in amyotrophic lateral sclerosis occurs more frequently in patients harboring an expansion in C9orf72. J. Neuropathol. Exp. Neurol. 73, 837–845 (2014).
doi: 10.1097/NEN.0000000000000102
Kerman, A. et al. Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathol. 119, 335–344 (2010).
doi: 10.1007/s00401-010-0646-5
Robinson, J. L. et al. TDP-43 skeins show properties of amyloid in a subset of ALS cases. Acta Neuropathol. 125, 121–131 (2013).
doi: 10.1007/s00401-012-1055-8
Lin, W. L. & Dickson, D. W. Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol. 116, 205–213 (2008).
doi: 10.1007/s00401-008-0408-9
Guenther, E. L. et al. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat. Struct. Mol. Biol. 25, 463–471 (2018).
doi: 10.1038/s41594-018-0064-2
Aguzzi, A., Heikenwalder, M. & Polymenidou, M. Insights into prion strains and neurotoxicity. Nat. Rev. Mol. Cell Biol. 8, 552–561 (2007).
doi: 10.1038/nrm2204
Yagi, H. et al. Zonisamide enhances neurite elongation of primary motor neurons and facilitates peripheral nerve regeneration in vitro and in a mouse model. PLoS One 10, e0142786 (2015).
doi: 10.1371/journal.pone.0142786
Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G. & Hengerer, B. Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J. Neurochem. 111, 192–203 (2009).
doi: 10.1111/j.1471-4159.2009.06324.x
Polymenidou, M. & Cleveland, D. W. Biological spectrum of amyotrophic lateral sclerosis prions. Cold Spring Harb. Perspect. Med. 7, a024133 (2017).
doi: 10.1101/cshperspect.a024133
Polymenidou, M. & Cleveland, D. W. The seeds of neurodegeneration: prion-like spreading in ALS. Cell 147, 498–508 (2011).
doi: 10.1016/j.cell.2011.10.011
Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).
doi: 10.1016/j.neuron.2014.04.047
Peelaerts, W. et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).
doi: 10.1038/nature14547
Meyer-Luehmann, M. et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).
doi: 10.1126/science.1131864
Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E. & Storey, J. D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882–883 (2012).
doi: 10.1093/bioinformatics/bts034
Ling, S. C. et al. ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc. Natl Acad. Sci. USA 107, 13318–13323 (2010).