Acta Neuropathologica

, Volume 138, Issue 5, pp 813–826 | Cite as

Splicing repression is a major function of TDP-43 in motor neurons

  • Aneesh Donde
  • Mingkuan Sun
  • Jonathan P. Ling
  • Kerstin E. Braunstein
  • Bo Pang
  • Xinrui Wen
  • Xueying Cheng
  • Liam ChenEmail author
  • Philip C. WongEmail author
Original Paper


Nuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression in Drosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.


Amyotrophic lateral sclerosis Cryptic exon Drosophila Motor neuron Mouse TDP-43 



We thank L. Martin, C. Sumner, and T. Lloyd for thoughtful comments and V. Nehus and H. Wu for technical assistance.

Author contributions

PCW, LC, AD and MS designed the experiments. JPL designed and cloned the constructs. AD and BP performed ICV injections. AD, BP, XW, and XC performed behavioral analyses in mice, and MS and LC in Drosophila. AD performed histological and RNA analysis in mice, and MS and LC in Drosophila. AD and KEB analyzed and interpreted data. AD, MS, LC, and PCW wrote the manuscript with the approval of all authors.


This work was supported by the NIH Grant No. R01 NS095969 (PCW), McKnight Memory and Cognitive Disorders Award (PCW and LC), Robert Packard Center for ALS Research (LC and PCW) and the Amyotrophic Lateral Sclerosis Association (PCW). JPL is a recipient of a Johns Hopkins Kavli Neuroscience Discovery Institute fellowship award.

Compliance with ethical standards

Conflict of interest

Authors declare no competing interests.

Supplementary material

401_2019_2042_MOESM1_ESM.tif (1.6 mb)
Figure S1. Sequencing validation of cryptic exon RT-PCR. (a) Diagram of RT-PCR detection strategy. Primers were designed to amplify only the cryptic exon splice junction. (b) Gel purification and sequencing of these RT-PCR bands confirms that these DNA products precisely correspond to the predicted cryptic exon splice junctions. (c) To visualize this, sequencing data was aligned to the Drosophila genome using UCSC BLAT; thick bands in the sequence alignment indicate DNA sequences that are present in the RT-PCR product, thin bands represent sequences that have been spliced out. Sequence alignment demonstrates clear overlap with cryptic exon and completely matches the predicted the splice junctions
401_2019_2042_MOESM2_ESM.tif (792 kb)
Figure S2. Expression of CTR in TBPH null flies. (a) Western blot confirmation of CTR expression. Both TBPHΔ23 homozygous null and the Hsp-70 CTR line lack the endogenous 58 KD TBPH protein as shown by the N-terminal TDP-43 antibody in wild type flies. Instead, the Hsp-70 CTR line expresses the shorter CTR fusion protein. Hsp-70 CTR expression level remains stable in aged flies as it is shown here at D30 after eclosion. (b) Immunofluorescent staining of CTR (red) and neuron-specific marker ELAV (nuclear, green) in third instar larval ventral nerve cord
401_2019_2042_MOESM3_ESM.tif (2.5 mb)
Figure S3. Morphological defects at neuromuscular synapsis in TBPH null flies. (a) Confocal images of motor neuron presynaptic terminals at abdominal segment III in wild type third instar larvae stained with anti-HRP (red) and anti-DLG (green) antibodies, reveals the branching pattern and the presence of synaptic boutons. (b) Similar staining and anatomical position show reduced axonal branching and number of synaptic boutons in TBPHΔ23 homozygous larvae. (c) Recovery of presynaptic complexity with increased formation of synaptic boutons and axonal terminal branching in Hsp-70 > CTR larvae
401_2019_2042_MOESM4_ESM.tif (684 kb)
Figure S4. Certain cryptic exon transcripts are not reversed in CTR rescue. Designing primers across cryptic exon sequences is difficult due to repetitive sequences. Therefore, high levels of background are inevitable. Nevertheless, relatively clean primers were identified for ten of the thirteen genes (Complete list of Drosophila cryptic exons is provided in Table S1), and their RT-PCR products can be clearly identified (red arrowheads). Four cryptic exon transcripts (rg, sev, Dyb, and Syn) were reversed in CTR rescue. The other six transcripts shown here were not completely reversed
401_2019_2042_MOESM5_ESM.tif (9.4 mb)
Figure S5. Expression of CTRF147L/F149L in TBPH-deficient flies has no rescue effect. (a) Diagram of the CTRF147L/F149L and UAS-NTDP chimeric constructs. Flagged CTRF147L/F149L strain did not express endogenous TBPH (b), nor did it extend lifespan (c), ameliorate locomotive function (d) or repress cryptic exon incorporations (e) in a homozygous TBPHΔ23 null background
401_2019_2042_MOESM6_ESM.tif (12.8 mb)
Figure S6. Immunofluorescent stain of ChAT (red) and TDP-43 (blue) in p30 ChAT-IRES-Cre;TardbpF/+ mice, CTR treated and untreated ChAT-IRES-Cre;tardbpF/F mice. In all three groups, Cre-dependent Tardbp knockout rate was ~ 95% in both cervical and lumbar sections and not significantly different between groups (mean difference in knockout rate = 1 ± 1.2%, p = 0.88, N = 5 mice per genotype, 5 cervical/lumbar sections per animal)
401_2019_2042_MOESM7_ESM.tif (1.8 mb)
Figure S7. Depletion of TDP-43 in lower motor neurons leads to age dependent motor deficits and early lethality in mice. (a) Kaplan–Meier survival curve of ChAT-IRES-Cre;tardbpF/+ (N = 22, 10♀) and ChAT-IRES-Cre;tardbpF/F (N = 14, 7♀) mice. Median untreated ChAT-IRES-Cre;tardbpF/F survival was 44 weeks in knockout mice. (b) Hanging wire, (c) body weight, and (d) rotarod performance are all impaired in ChAT-IRES-Cre;tardbpF/F mice. (p < 0.001 for all analyses)
401_2019_2042_MOESM8_ESM.tif (521 kb)
Figure S8. Body weights for CTR treated and untreated ChAT-IRES-Cre;TardbpF/+ and ChAT-IRES-Cre;tardbpF/F mice, separated by sex (* p < 0.05)
401_2019_2042_MOESM9_ESM.tif (11.3 mb)
Figure S9. N-terminal fragment expression alone confers no therapeutic benefit in Tardbp knockout mice. (a) Hanging wire performance and (b) body weights of ChAT-IRES-Cre;tardbpF/F mice administered AAV9 containing the N-terminal fragment of TDP-43 alone (NTF, blue) showed no improvement over untreated littermates (red). (c) NTF treated ChAT-IRES-Cre;tardbpF/F mice also showed no restoration of splicing repression as evidenced by cryptic exon incorporation into 3 targets tested
401_2019_2042_MOESM10_ESM.tif (5.9 mb)
Figure S10. Quantification of ChAT-positive motor neurons in CTR-treated (blue) and untreated (red) knockout mice at 1 months’ age (a) and 5 months’ age (b). As no difference was observed between motor neuron numbers of CTR-treated and untreated ChAT-IRES-Cre;TardbpF/+ mice at any time point, results are shown as a percentage of each group’s respective control. While no changes were observed at the 1-month time point, untreated knockout mice showed a decrease in motor neuron number at 5 months’ age to 47% of that of controls. The motor neuron abundance of CTR-treated knockout mice is 54% (lumbar) and 56% (cervical) of controls (*p < 0.05)
401_2019_2042_MOESM11_ESM.tif (9 mb)
Figure S11. (a) RT-PCR amplification of abnormal Sort1 splicing variant including exon 17b in mouse spinal cord and hippocampus. Like Tbc1d1, aberrant splicing of Sort1 was not observed in mouse motor neurons, but appeared in hippocampal neurons due to the depletion of TDP-43 which could be restored with the treatment of CTR. Lane 1: ChaT-IRES-Cre;TardbpF/+; lane 2: ChaT-IRES-Cre;TardbpF/F; lane 3: CTR-treated ChaT-IRES-Cre;TardbpF/F mice; lane 4: CamK2a-Cre;tardbpF/+; lane 5: CamK2a-Cre;tardbpF/F; lane 6: CTR-treated CamK2a-Cre;tardbpF/F mice. (b) Confocal images showing reduced Futsch (green) expression in the distal boutons (HRP, red) of TBPHΔ23/Δ23 flies (ii) compared with wild type (i). This defect could not be reversed by the expression of CTR fusion protein (iii). Scale bar: 10 µm
401_2019_2042_MOESM12_ESM.docx (14 kb)
Table S1. List of cryptic exons identified in TBPH-deficient Drosophila
401_2019_2042_MOESM13_ESM.docx (13 kb)
Table S2. Final sample sizes for all mouse cohorts examined in this study, separated by genotype and injection type

Movie S1. Representative video of p90 untreated ChAT-IRES-Cre;tardbpF/F mice (left cage) and a CTR-treated ChAT-IRES-Cre;tardbpF/F mouse (right cage). At the end of the video, a representative ChAT-IRES-Cre;TardbpF/+ mouse is shown as well. The improvement in motor function in CTR-treated Tardbp knockout mice is evident by the increased locomotion and hindlimb mobility


  1. 1.
    Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SSW et al (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81:536–543. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ash PE, Zhang YJ, Roberts CM, Saldi T, Hutter H, Buratti E et al (2010) Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 19:3206–3218. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ayala YM, De Conti L, Avendano-Vazquez SE, Dhir A, Romano M, D’Ambrogio A et al (2011) TDP-43 regulates its mRNA levels through a negative feedback loop. The EMBO J 30:277–288. CrossRefPubMedGoogle Scholar
  5. 5.
    Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P et al (2017) Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544:367–371. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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 276:36337–36343. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. The EMBO J 20:1774–1784. CrossRefPubMedGoogle Scholar
  8. 8.
    Casafont I, Bengoechea R, Tapia O, Berciano MT, Lafarga M (2009) TDP-43 localizes in mRNA transcription and processing sites in mammalian neurons. J Struct Biol 167:235–241. CrossRefPubMedGoogle Scholar
  9. 9.
    Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M et al (2015) Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348:1151–1154. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chiang PM, Ling J, Jeong YH, Price DL, Aja SM, Wong PC (2010) 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. CrossRefPubMedGoogle Scholar
  11. 11.
    Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F et al (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci 21:228–239. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Duffy JB (2002) GAL4 system in Drosophila: a fly geneticist’s Swiss army knife. Genesis 34:1–15. CrossRefPubMedGoogle Scholar
  13. 13.
    Ehrmann I, Crichton JH, Gazzara MR, James K, Liu Y, Grellscheid SN et al (2019) An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning. Elife. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Feiguin F, Godena VK, Romano G, D’Ambrogio A, Klima R, Baralle FE (2009) Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583:1586–1592. CrossRefPubMedGoogle Scholar
  15. 15.
    Fiesel FC, Voigt A, Weber SS, Van den Haute C, Waldenmaier A, Gorner K et al (2010) Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6. The EMBO J 29:209–221. CrossRefPubMedGoogle Scholar
  16. 16.
    Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM et al (2010) Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 28:271–274. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Freibaum BD, Chitta RK, High AA, Taylor JP (2010) Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9:1104–1120. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    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. CrossRefGoogle Scholar
  19. 19.
    Gopal PP, Nirschl JJ, Klinman E, Holzbaur EL (2017) 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. CrossRefPubMedGoogle Scholar
  20. 20.
    Gromak N, Rideau A, Southby J, Scadden AD, Gooding C, Huttelmaier S et al (2003) The PTB interacting protein raver1 regulates alpha-tropomyosin alternative splicing. The EMBO J 22:6356–6364. CrossRefPubMedGoogle Scholar
  21. 21.
    Guo L, Kim HJ, Wang H, Monaghan J, Freyermuth F, Sung JC et al (2018) Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173(677–692):e620. CrossRefGoogle Scholar
  22. 22.
    Huang YC, Lin KF, He RY, Tu PH, Koubek J, Hsu YC et al (2013) Inhibition of TDP-43 aggregation by nucleic acid binding. PLoS One 8:e64002. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hudry E, Vandenberghe LH (2019) Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron 102:263. CrossRefPubMedGoogle Scholar
  24. 24.
    Iguchi Y, Katsuno M, Niwa J, Takagi S, Ishigaki S, Ikenaka K et al (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136:1371–1382. CrossRefPubMedGoogle Scholar
  25. 25.
    Jeong YH, Ling JP, Lin SZ, Donde AN, Braunstein KE, Majounie E et al (2017) Tdp-43 cryptic exons are highly variable between cell types. Mol Neurodegener 12:13. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574. CrossRefGoogle Scholar
  27. 27.
    Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA, Trojanowski JQ et al (2014) Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet 46:152–160. CrossRefPubMedGoogle Scholar
  28. 28.
    Klim JR, Williams LA, Limone F, Guerra San Juan I, Davis-Dusenbery BN, Mordes DA et al (2019) ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci 22:167–179. CrossRefPubMedGoogle Scholar
  29. 29.
    LaClair KD, Donde A, Ling JP, Jeong YH, Chhabra R, Martin LJ et al (2016) Depletion of TDP-43 decreases fibril and plaque beta-amyloid and exacerbates neurodegeneration in an Alzheimer’s mouse model. Acta neuropathologica. (SQSTM1/p62859–62873) CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lee EB, Lee VM, Trojanowski JQ (2011) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13:38–50. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Li Z, Vuong JK, Zhang M, Stork C, Zheng S (2017) Inhibition of nonsense-mediated RNA decay by ER stress. RNA 23:378–394. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ling JP, Chhabra R, Merran JD, Schaughency PM, Wheelan SJ, Corden JL et al (2016) PTBP1 and PTBP2 repress nonconserved cryptic exons. Cell Rep 17:104–113. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ling JP, Pletnikova O, Troncoso JC, Wong PC (2015) TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349:650–655. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lukavsky PJ, Daujotyte D, Tollervey JR, Ule J, Stuani C, Buratti E et al (2013) Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. Nat Struct Mol Biol 20:1443–1449. CrossRefPubMedGoogle Scholar
  35. 35.
    Mann JR, Gleixner AM, Mauna JC, Gomes E, DeChellis-Marks MR, Needham PG et al (2019) RNA binding antagonizes neurotoxic phase transitions of TDP-43. Neuron 102(321–338):e328. CrossRefGoogle Scholar
  36. 36.
    McClory SP, Lynch KW, Ling JP (2018) HnRNP L represses cryptic exons. RNA 24:761–768. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    McDonald KK, Aulas A, Destroismaisons L, Pickles S, Beleac E, Camu W et al (2011) TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet 20:1400–1410. CrossRefPubMedGoogle Scholar
  38. 38.
    McGurk L, Gomes E, Guo L, Mojsilovic-Petrovic J, Tran V, Kalb RG et al (2018) Poly(ADP-Ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol Cell 71(703–717):e709. CrossRefGoogle Scholar
  39. 39.
    Melamed Z, Lopez-Erauskin J, Baughn MW, Zhang O, Drenner K, Sun Y et al (2019) Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci 22:180–190. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW et al (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377:1713–1722. CrossRefPubMedGoogle Scholar
  41. 41.
    Mitra J, Guerrero EN, Hegde PM, Liachko NF, Wang H, Vasquez V et al (2019) Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proc Natl Acad Sci USA. CrossRefPubMedGoogle Scholar
  42. 42.
    Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ et al (2015) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163:123–133. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nana AL, Sidhu M, Gaus SE, Hwang JL, Li L, Park Y et al (2019) Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology. Acta Neuropathol 137:27–46. CrossRefPubMedGoogle Scholar
  44. 44.
    Neumann M, Kwong LK, Truax AC, Vanmassenhove B, Kretzschmar HA, Van Deerlin VM et al (2007) TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J Neuropathol Exp Neurol 66:177–183. CrossRefPubMedGoogle Scholar
  45. 45.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY et al (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14:459–468. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Prudencio M, Belzil VV, Batra R, Ross CA, Gendron TF, Pregent LJ et al (2015) Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat Neurosci 18:1175–1182. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Rideau AP, Gooding C, Simpson PJ, Monie TP, Lorenz M, Huttelmaier S et al (2006) A peptide motif in Raver1 mediates splicing repression by interaction with the PTB RRM2 domain. Nat Struct Mol Biol 13:839–848. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Romano M, Feiguin F, Buratti E (2016) TBPH/TDP-43 modulates translation of Drosophila futsch mRNA through an UG-rich sequence within its 5′UTR. Brain Res 1647:50–56. CrossRefPubMedGoogle Scholar
  51. 51.
    Rossi J, Balthasar N, Olson D, Scott M, Berglund E, Lee CE et al (2011) Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab 13:195–204. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Schmid B, Hruscha A, Hogl S, Banzhaf-Strathmann J, Strecker K, van der Zee J et al (2013) Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci USA 110:4986–4991. CrossRefPubMedGoogle Scholar
  54. 54.
    Sephton CF, Good SK, Atkin S, Dewey CM, Mayer P 3rd, Herz J et al (2010) TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285:6826–6834. CrossRefPubMedGoogle Scholar
  55. 55.
    Shan X, Chiang PM, Price DL, Wong PC (2010) 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. CrossRefPubMedGoogle Scholar
  56. 56.
    Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672. CrossRefGoogle Scholar
  57. 57.
    Sun M, Bell W, LaClair KD, Ling JP, Han H, Kageyama Y et al (2017) Cryptic exon incorporation occurs in Alzheimer’s brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. Acta Neuropathol 133:923–931. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Tan Q, Yalamanchili HK, Park J, De Maio A, Lu HC, Wan YW et al (2016) Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Hum Mol Genet 25:5083–5093. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Taylor JP, Brown RH Jr, Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539:197–206. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Uemura Y, Oshima T, Yamamoto M, Reyes CJ, Costa Cruz PH, Shibuya T et al (2017) Matrin3 binds directly to intronic pyrimidine-rich sequences and controls alternative splicing. Genes Cells 22:785–798. CrossRefPubMedGoogle Scholar
  62. 62.
    Vatsavayai SC, Yoon SJ, Gardner RC, Gendron TF, Vargas JN, Trujillo A et al (2016) Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139:3202–3216. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    White MA, Kim E, Duffy A, Adalbert R, Phillips BU, Peters OM et al (2018) TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nat Neurosci 21:552–563. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I et al (2010) 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. CrossRefPubMedGoogle Scholar
  65. 65.
    Wu LS, Cheng WC, Hou SC, Yan YT, Jiang ST, Shen CK (2010) TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48:56–62. CrossRefPubMedGoogle Scholar
  66. 66.
    Wu LS, Cheng WC, Shen CK (2012) Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem 287:27335–27344. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Xu YF, Gendron TF, Zhang YJ, Lin WL, D’Alton S, Sheng H et al (2010) 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. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Yang C, Wang H, Qiao T, Yang B, Aliaga L, Qiu L et al (2014) Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 111:E1121–E1129. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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