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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

Abstract

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.

Keywords

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

Notes

Acknowledgements

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.

Funding

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

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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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