- Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006). TDP43 protein is identified biochemically, immunohistochemically and by amino acid sequence analysis as the major component of proteinaceous ubiquitin-positive inclusions in FTLD and ALS. Pathologic TDP43 is found to be ubiquitylated, phosphorylated and cleaved, and is associated with nuclear clearance of normal TDP43.
Article CAS PubMed Google Scholar
- Giordana, M. T. et al. TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis. Brain Pathol. 20, 351–360 (2010).
Article CAS PubMed Google Scholar
- Brandmeir, N. J. et al. Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Acta Neuropathol. 115, 123–131 (2008).
Article PubMed Google Scholar
- Strong, M. J. et al. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol. Cell. Neurosci. 35, 320–327 (2007).
Article CAS PubMed Google Scholar
- Pamphlett, R., Luquin, N., McLean, C., Jew, S. K. & Adams, L. TDP-43 neuropathology is similar in sporadic amyotrophic lateral sclerosis with or without TDP-43 mutations. Neuropathol. Appl. Neurobiol. 35, 222–225 (2009).
Article CAS PubMed Google Scholar
- Dickson, D. W., Josephs, K. A. & Amador-Ortiz, C. TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol. 114, 71–79 (2007).
Article CAS PubMed Google Scholar
- Davidson, Y. et al. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol. 113, 521–533 (2007).
Article CAS PubMed Google Scholar
- Cairns, N. J. et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am. J. Pathol. 171, 227–240 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Fujita, Y., Mizuno, Y., Takatama, M. & Okamoto, K. Anterior horn cells with abnormal TDP-43 immunoreactivities show fragmentation of the Golgi apparatus in ALS. J. Neurol. Sci. 269, 30–34 (2008).
Article CAS PubMed Google Scholar
- Mori, F. et al. Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol. 116, 193–203 (2008).
Article CAS PubMed Google Scholar
- Pesiridis, G. S., Lee, V. M. & Trojanowski, J. Q. Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. Hum. Mol. Genet. 18, R156–R162 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Gitcho, M. A. et al. TDP-43 A315T mutation in familial motor neuron disease. Ann. Neurol. 63, 535–538 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nature Genet. 40, 572–574 (2008).
Article CAS PubMed Google Scholar
- Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008). The first of several reports identifying TARDBP missense mutations, confirming the role of TDP43 in both sporadic and familial ALS.
Article CAS PubMed PubMed Central Google Scholar
- Van Deerlin, V. M. et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 7, 409–416 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Mackenzie, I. R., Rademakers, R. & Neumann, M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995–1007 (2010).
Article CAS PubMed Google Scholar
- Geser, F., Lee, V. M. & Trojanowski, J. Q. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 30, 103–112 (2010).
Article PubMed PubMed Central Google Scholar
- Da Cruz, S. & Cleveland, D. W. Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr. Opin. Neurobiol. 1 Aug 2011 (doi:10.1016/j.conb.2011.05.029).
Article CAS PubMed PubMed Central Google Scholar
- Lagier-Tourenne, C., Polymenidou, M. & Cleveland, D. W. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum. Mol. Genet. 19, R46–R64 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Ward, M. E. & Miller, B. L. Potential mechanisms of progranulin-deficient FTLD. J. Mol. Neurosci. 3 Sept 2011 (doi:10.1007/s12031-011-9622-3).
Article CAS PubMed Google Scholar
- Ayala, Y. M. et al. Human, Drosophila, and C.elegans TDP43: nucleic acid binding properties and splicing regulatory function. J. Mol. Biol. 348, 575–588 (2005).
Article CAS PubMed Google Scholar
- Ou, S. H., Wu, F., Harrich, D., Garcia-Martinez, L. F. & Gaynor, R. B. Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J. Virol. 69, 3584–3596 (1995).
CAS PubMed PubMed Central Google Scholar
- Wang, H. Y., Wang, I. F., Bose, J. & Shen, C. K. Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83, 130–139 (2004).
Article CAS PubMed Google Scholar
- Buratti, E. & Baralle, F. E. 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, 36337–36343 (2001). Functional anlaysis of TDP43 protein as an RNA-binding protein that regulates alternative splicing of pre-mRNA.
Article CAS PubMed Google Scholar
- Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nature Neurosci. 14, 459–468 (2011). The identification of RNA molecules that physically interact with TDP43 protein using HITS-CLIP analysis. Binding of a large proportion of the transcriptome is observed, including binding of the TDP43 RNA itself, and this is mechanistically linked to autoregulation.
Article CAS PubMed Google Scholar
- Buratti, E., Brindisi, A., Pagani, F. & Baralle, F. E. Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. Am. J. Hum. Genet. 74, 1322–1325 (2004).
Article CAS PubMed PubMed Central Google Scholar
- Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nature Neurosci. 14, 452–458 (2011).
Article CAS PubMed Google Scholar
- Buratti, E. et al. TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J. Biol. Chem. 280, 37572–37584 (2005). A study of the interaction between the C terminus of TDP43 and other members of the hnRNP complex, including hnRNP A2/B1 and hnRNP A1. This paper also shows that TDP43 regulates splicing in the early stages of spliceosomal assembly.
Article CAS PubMed Google Scholar
- Ling, S. C. et al. ALS-associated mutations in TDP-43 increase its stability and promote complexes with FUS/TLS. Proc. Natl Acad. Sci. USA 107, 13318–13323 (2010). A proteomic analysis of proteins found in complex with TDP43, which includes the hnRNP proteins, FUS protein and components of the Drosha microprocessor complex. ALS-associated mutations increase the interaction between TDP43 and FUS.
Article CAS PubMed PubMed Central Google Scholar
- Freibaum, B. D., Chitta, R. K., High, A. A. & Taylor, J. P. Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J. Proteome Res. 9, 1104–1120 (2010).
Article CAS PubMed PubMed Central Google Scholar
- D'Ambrogio, A. et al. Functional mapping of the interaction between TDP-43 and hnRNP A2 in vivo. Nucleic Acids Res. 37, 4116–4126 (2009).
Article CAS PubMed PubMed Central Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Bose, J. K., Wang, I. F., Hung., L., Tarn, W. Y. & Shen, C. K. TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. J. Biol. Chem. 283, 28852–28859 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Mercado, P. A., Ayala, Y. M., Romano, M., Buratti, E. & Baralle, F. E. Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res. 33, 6000–6010 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Dreumont, N. et al. Antagonistic factors control the unproductive splicing of SC35 terminal intron. Nucleic Acids Res. 38, 1353–1366 (2010).
Article CAS PubMed Google Scholar
- Ayala, Y. M., Misteli, T. & Baralle, F. E. TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression. Proc. Natl Acad. Sci. USA 105, 3785–3789 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Fiesel, F. C. et al. Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6. EMBO J. 29, 209–221 (2010).
Article CAS PubMed Google Scholar
- Godena, V. K. et al. TDP-43 regulates Drosophila neuromuscular junctions growth by modulating Futsch/MAP1B levels and synaptic microtubules organization. PloS ONE 6, e17808 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Wang, I. F., Wu, L. S., Chang, H. Y. & Shen, C. K. TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J. Neurochem. 105, 797–806 (2008).
Article CAS PubMed Google Scholar
- Elvira, G. et al. Characterization of an RNA granule from developing brain. Mol. Cell. Proteomics 5, 635–651 (2006).
Article CAS PubMed Google Scholar
- Moisse, K. et al. Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-/- mice: support for a role for TDP-43 in the physiological response to neuronal injury. Brain Res. 1296, 176–186 (2009).
Article CAS PubMed Google Scholar
- Moisse, K. et al. Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res. 1249, 202–211 (2009).
Article CAS PubMed Google Scholar
- Sato, T. et al. Axonal ligation induces transient redistribution of TDP-43 in brainstem motor neurons. Neuroscience 164, 1565–1578 (2009).
Article CAS PubMed Google Scholar
- Nishimoto, Y. et al. Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43. J. Biol. Chem. 285, 608–619 (2010).
Article CAS PubMed Google Scholar
- Colombrita, C. et al. TDP-43 is recruited to stress granules in conditions of oxidative insult. J. Neurochem. 111, 1051–1061 (2009).
Article CAS PubMed Google Scholar
- Volkening, K., Leystra-Lantz, C., Yang, W., Jaffee, H. & Strong, M. J. Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS). Brain Res. 1305, 168–182 (2009).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed Google Scholar
- McDonald, K. K. et al. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum. Mol. Genet. 20, 1400–10 (2011).
Article CAS PubMed Google Scholar
- Casafont, I., Bengoechea, R., Tapia, O., Berciano, M. T. & Lafarga, M. TDP-43 localizes in mRNA transcription and processing sites in mammalian neurons. J. Struct. Biol. 167, 235–241 (2009).
Article CAS PubMed Google Scholar
- Buratti, E. et al. Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J. 277, 2268–2281 (2010).
Article CAS PubMed Google Scholar
- Fukuda, T. et al. DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs. Nature Cell Biol. 9, 604–611 (2007).
Article CAS PubMed Google Scholar
- Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
Article CAS PubMed Google Scholar
- Acharya, K. K., Govind, C. K., Shore, A. N., Stoler, M. H. & Reddi, P. P. cis-requirement for the maintenance of round spermatid-specific transcription. Dev. Biol. 295, 781–790 (2006).
Article CAS PubMed Google Scholar
- Kuo, P. H., Doudeva, L. G., Wang, Y. T., Shen, C. K. & Yuan, H. S. Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Res. 37, 1799–1808 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Abhyankar, M. M., Urekar, C. & Reddi, P. P. A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function. J. Biol. Chem. 282, 36143–36154 (2007).
Article CAS PubMed Google Scholar
- Furukawa, Y., Kaneko, K., Watanabe, S., Yamanaka, K. & Nukina, N. A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J. Biol. Chem. 286, 18664–18672 (2011).
Article CAS PubMed PubMed Central Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Hasegawa, M. et al. Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann. Neurol. 64, 60–70 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011). The identification of dominant mutations in UBQLN2 that are associated with X-linked juvenile and adult-onset ALS and ALS-dementia. The results implicate abnormal protein degradation pathways in the pathogenesis of motor neuron disease.
Article CAS PubMed PubMed Central Google Scholar
- Shan, X., Chiang, P. M., Price, D. L. & Wong, P. C. Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc. Natl Acad. Sci. USA 107, 16325–16330 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Stallings, N. R., Puttaparthi, K., Luther, C. M., Burns, D. K. & Elliott, J. L. Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol. Dis. 40, 404–414 (2010).
Article CAS PubMed Google Scholar
- Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M. & Baloh, R. H. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 106, 18809–18814 (2009). The first transgenic mouse overexpressing TDP43 is described. It demonstrates selective neurodegeneration and death, recapitulating many of the major features of ALS and FTLD
Article CAS PubMed PubMed Central Google Scholar
- Wils, H. et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 107, 3858–3863 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Xu, Y. F. et al. Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J. Neurosci. 30, 10851–10859 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Igaz, L. M. et al. Expression of TDP-43 c-terminal fragments in vitro recapitulates pathological features of TDP-43 proteinopathies. J. Biol. Chem. 284, 8516–8524 (2009). This paper shows that overexpression of disease-associated C-terminal TDP43 fragments leads to cytoplasmic aggregation. The aggregates are ubiquitylated and phosphorylated. These changes are associated with changes in RNA splicing.
Article CAS PubMed PubMed Central Google Scholar
- Igaz, L. M. et al. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J. Clin. Invest. 121, 726–738 (2011). Overexpression of nuclear or cytoplasmic human TDP43 protein in transgenic mice results in selective neurodegeneration recapitulating many of the major features of FTLD and upper motor neuron disease. Transgene expression leads to downregulation of endogenous TDP43 mRNA and protein, and this autoregulation phenomenon is the best correlate of neurodegeneration.
Article CAS PubMed PubMed Central Google Scholar
- Nonaka, T. et al. Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells. FEBS Lett. 583, 394–400 (2009).
Article CAS PubMed Google Scholar
- Nonaka, T., Kametani, F., Arai, T., Akiyama, H. & Hasegawa, M. Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. Hum. Mol. Genet. 18, 3353–3364 (2009).
Article CAS PubMed Google Scholar
- Winton, M. J. et al. Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J. Biol. Chem. 283, 13302–13309 (2008). This paper shows that overexpression of TDP43 protein harbouring mutations of the NLS domain results in cytoplasmic TDP43 protein that accumulates as cytoplasmic aggregates, implicating abnormal TDP43 protein localization in the pathogenesis of ALS and FTLD
Article CAS PubMed PubMed Central Google Scholar
- Zhang, Y. J. et al. Phosphorylation regulates proteasomal-mediated degradation and solubility of TAR DNA binding protein-43 C-terminal fragments. Mol. Neurodegener. 5, 33 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Pesiridis, G. S., Tripathy, K., Tanik, S., Trojanowski, J. Q. & Lee, V. M. A “Two-hit” hypothesis for inclusion formation by carboxyl-terminal fragments of TDP-43 protein linked to RNA depletion and impaired microtubule-dependent transport. J. Biol. Chem. 286, 18845–18855 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Urushitani, M., Sato, T., Bamba, H., Hisa, Y. & Tooyama, I. Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP-43. J. Neurosci. Res. 88, 784–797 (2010).
CAS PubMed Google Scholar
- Kim, S. H. et al. Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1. J. Biol. Chem. 284, 8083–8092 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Brady, O. A., Meng, P., Zheng, Y., Mao, Y. & Hu, F. Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1. J. Neurochem. 116, 248–259 (2011).
Article CAS PubMed Google Scholar
- Filimonenko, M. et al. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell Biol. 179, 485–500 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Wang, X. et al. Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. Neurosci. Lett. 469, 112–116 (2010).
Article CAS PubMed Google Scholar
- Suzuki, S. et al. AMSH is required to degrade ubiquitinated proteins in the central nervous system. Biochem. Biophys. Res. Commun. 408, 582–588 (2011).
Article CAS PubMed Google Scholar
- Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nature Genet. 37, 806–808 (2005).
Article CAS PubMed Google Scholar
- Hanson, K. A., Kim, S. H., Wassarman, D. A. & Tibbetts, R. S. Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). J. Biol. Chem. 285, 11068–11072 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Liachko, N. F., Guthrie, C. R. & Kraemer, B. C. Phosphorylation promotes neurotoxicity in a Caenorhabditis elegans model of TDP-43 proteinopathy. J. Neurosci. 30, 16208–16219 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Dormann, D. et al. Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin. J. Neurochem. 110, 1082–1094 (2009).
Article CAS PubMed Google Scholar
- Zhang, Y. J. et al. Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc. Natl Acad. Sci. USA 106, 7607–7612 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Sampathu, D. M. et al. Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am. J. Pathol. 169, 1343–1352 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Mackenzie, I. R. et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 122, 111–113 (2011).
Article PubMed PubMed Central Google Scholar
- Mackenzie, I. R. et al. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol. 112, 539–549 (2006).
Article PubMed PubMed Central Google Scholar
- Johnson, B. S. et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J. Biol. Chem. 284, 20329–20339 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Frost, B., Ollesch, J., Wille, H. & Diamond, M. I. Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J. Biol. Chem. 284, 3546–3551 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Guo, J. L. & Lee, V. M. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem. 286, 15317–15331 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Hansen, C. et al. α-synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715–725 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Luk, K. C. et al. Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl Acad. Sci. USA 106, 20051–20056 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Cushman, M., Johnson, B. S., King, O. D., Gitler, A. D. & Shorter, J. Prion-like disorders: blurring the divide between transmissibility and infectivity. J. Cell Sci. 123, 1191–1201 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Gitler, A. D. & Shorter, J. RNA-binding proteins with prion-like domains in ALS and FTLD-U. Prion 5, 179–187 (2011). A review of recent characterization of prion-like domains within TDP43 and FUS, and the implications of such domains in the progression of disease.
Article CAS PubMed PubMed Central Google Scholar
- Guo, W. et al. An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nature Struct. Mol. Biol. 18, 822–830 (2011).
Article CAS Google Scholar
- Fuentealba, R. A. et al. Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43. J. Biol. Chem. 285, 26304–26314 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Nishihira, Y. et al. Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. Acta Neuropathol. 117, 45–53 (2009).
Article CAS PubMed Google Scholar
- Pamphlett, R. & Kum Jew, S. TDP-43TDP43 inclusions do not protect motor neurons from sporadic ALS. Acta Neuropathol. 116, 221–222 (2008).
Article PubMed Google Scholar
- Braun, R. J. et al. Neurotoxic 43-kDa TAR DNA-binding protein (TDP-43) triggers mitochondrion-dependent programmed cell death in yeast. J. Biol. Chem. 286, 19958–19972 (2011).
Article CAS PubMed PubMed Central Google Scholar
- 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).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Rutherford, N. J. et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 4, e1000193 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Zhang, Y. J. et al. Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J. Neurosci. 27, 10530–10534 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Caccamo, A. et al. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J. Biol. Chem. 284, 27416–27424 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Tsai, K. J. et al. Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J. Exp. Med. 207, 1661–1673 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Yang, C. et al. The C-terminal TDP-43 fragments have a high aggregation propensity and harm neurons by a dominant-negative mechanism. PloS ONE 5, e15878 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Li, Y. et al. A Drosophila model for TDP-43 proteinopathy. Proc. Natl Acad. Sci. USA 107, 3169–3174 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Voigt, A. et al. TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PloS ONE 5, e12247 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Ayala, Y. M. et al. Structural determinants of the cellular localization and shuttling of TDP-43. J. Cell Sci. 121, 3778–3785 (2008).
Article CAS PubMed Google Scholar
- Thorpe, J. R., Tang, H., Atherton, J. & Cairns, N. J. Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. J. Neural Transm. 115, 1661–1671 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Winton, M. J. et al. A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Lett. 582, 2252–2256 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Luty, A. A. et al. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann. Neurol. 68, 639–649 (2010).
Article CAS PubMed Google Scholar
- Ritson, G. P. et al. TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J. Neurosci. 30, 7729–7739 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Barmada, S. J. et al. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J. Neurosci. 30, 639–649 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Miguel, L., Frebourg, T., Campion, D. & Lecourtois, M. Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies. Neurobiol. Dis. 41, 398–406 (2011).
Article CAS PubMed Google Scholar
- DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).
Article CAS PubMed Google Scholar
- Chiang, P. M. et al. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc. Natl Acad. Sci. USA 107, 16320–16324 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Ayala, Y. M. et al. TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J. 30, 277–288 (2011). A molecular analysis of the mechanisms of TDP43 autoregulation, including identification of the 3′ UTR binding site and the role of exosome-mediated RNA decay. Nonsense-mediated decay is not implicated in this process.
Article CAS PubMed Google Scholar
- Iguchi, Y. et al. TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases. J. Biol. Chem. 284, 22059–22066 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Feiguin, F. et al. Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett. 583, 1586–1592 (2009).
Article CAS PubMed Google Scholar
- Kabashi, E. et al. Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum. Mol. Genet. 19, 671–683 (2010).
Article CAS PubMed Google Scholar
- Sephton, C. F. et al. TDP-43 is a developmentally regulated protein essential for early embryonic development. J. Biol. Chem. 285, 6826–6834 (2010).
Article CAS PubMed Google Scholar
- Wu, L. S. et al. TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48, 56–62 (2010).
CAS PubMed Google Scholar
- Kraemer, B. C. et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 119, 409–419 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Kwiatkowski, T. J., Jr. et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009). The identification of FUS mutations associated with familial ALS. As FUS is an RNA-binding protein, this discovery further supports the hypothesis that aberrant RNA processing is involved in the pathogenesis of ALS and FTLD.
Article CAS PubMed Google Scholar
- Deng, H. X. et al. Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261, 1047–1051 (1993).
Article CAS PubMed Google Scholar
- Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).
Article CAS PubMed Google Scholar
- Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).
Article CAS PubMed Google Scholar
- Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006).
Article CAS PubMed Google Scholar
- Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nature Genet. 36, 377–381 (2004).
Article CAS PubMed Google Scholar
- Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010). Based on data from a yeast genetic screen, this paper identifies intermediate-sized polyglutamine repeats as a risk factor for developing ALS in humans.
Article CAS PubMed PubMed Central Google Scholar
- Al-Saif, A., Al-Mohanna, F. & Bohlega, S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann. Neurol. 12 Aug 2011 (doi:10.1002/ana.22534).
Article CAS PubMed Google Scholar
- Dejesus-Hernandez, M. & al., E. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). In this paper, a hexanucleotide repeat expansion in C9ORF72 is found to result in ALS, and this mutation accounts for the majority of familial ALS cases. The repeat expansion results in both altered splicing of the C9ORF72 transcript and the formation of nuclear C9ORF72 RNA foci.
Article CAS PubMed PubMed Central Google Scholar
- Renton, A. E. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). This study and reference 131 reported hexanucleotide repeat expansions in C9ORF72 that are pathogenic for ALS.
Article CAS PubMed PubMed Central Google Scholar
- Mackenzie, I. R. et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann. Neurol. 61, 427–434 (2007). TDP43 pathology is seen in both sporadic and familial ALS cases, except in ALS cases that are associated with SOD1 mutations. This report suggests that cases that are associated with SOD1 mutations may involve a distinct disease process.
Article CAS PubMed Google Scholar
- Sun, Z. et al. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol. 9, e1000614 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Lanson, N. A., Jr. et al. A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Hum. Mol. Genet. 12 Apr 2011 (doi:10.1093/hmg/ddr150).
Article CAS PubMed PubMed Central Google Scholar
- Wang, J. W., Brent, J. R., Tomlinson, A., Shneider, N. A. & McCabe, B. D. The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span. J. Clin. Invest. 121, 4118–4126 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Wojciechowska, M. & Krzyzosiak, W. J. Cellular toxicity of expanded RNA repeats: focus on RNA foci. Human Mol. Genet. 20, 3811–3821 (2011).
Article CAS Google Scholar
- Yu, Z. et al. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PloS ONE 6, e17951 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Glenner, G. G. & Wong, C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).
Article CAS PubMed Google Scholar
- Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).
Article CAS PubMed Google Scholar
- Chartier-Harlin, M. C. et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–846 (1991).
Article CAS PubMed Google Scholar
- Murrell, J., Farlow, M., Ghetti, B. & Benson, M. D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254, 97–99 (1991).
Article CAS PubMed Google Scholar
- Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).
Article CAS PubMed Google Scholar
- Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).
Article CAS PubMed Google Scholar
- Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer's disease: the challenge of the second century. Sci. Transl. Med. 3, 77sr1 (2011).
PubMed PubMed Central Google Scholar
- Knopman, D. S., Mastri, A. R., Frey, W. H., 2nd, Sung, J. H. & Rustan, T. Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 40, 251–256 (1990).
Article CAS PubMed Google Scholar
- Mackenzie, I. R. et al. Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol. 112, 551–559 (2006).
Article PubMed Google Scholar
- Mackenzie, I. R. et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 119, 1–4 (2010).
Article PubMed Google Scholar