Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Nature Communications

Volumn 6, Issue , 2015, Pages

  Devlin, Anna Claire ^a,b   Burr, Karen ^b,c   Borooah, Shyamanga ^b,c   Foster, Joshua D ^a   Cleary, Elaine M ^b,c   Geti, Imbisaat ^d   Vallier, Ludovic ^d   Shaw, Christopher E ^e   Chandran, Siddharthan ^b,c   Miles, Gareth B ^a,b  

^a UNIVERSITY OF ST ANDREWS   (United Kingdom)

^b Euan MacDonald Centre for Motor Neuron Disease Research   (United Kingdom)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

^d UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^e KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

MUTATION; NEUROLOGY; VIABILITY;

ACTION POTENTIAL; AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; C9ORF72 GENE; CELL VIABILITY; CLINICAL ARTICLE; CONTROLLED STUDY; ELECTROPHYSIOLOGY; FEMALE; GENOTYPE; HUMAN; HUMAN CELL; MALE; MOTONEURON; MUTATOR GENE; PATHOPHYSIOLOGY; PLURIPOTENT STEM CELL; POTASSIUM CURRENT; SODIUM CURRENT; TARDBP GENE; CELL LINE; CELL SURVIVAL; CHEMISTRY; GENETICS; INDUCED PLURIPOTENT STEM CELL; METABOLISM; MUTATION; OPEN READING FRAME; PATCH CLAMP TECHNIQUE; PATHOLOGY;

C9ORF72 PROTEIN, HUMAN; DNA BINDING PROTEIN; POTASSIUM; PROTEIN; SODIUM; TDP-43 PROTEIN, HUMAN;

ACTION POTENTIALS; AMYOTROPHIC LATERAL SCLEROSIS; CELL LINE; CELL SURVIVAL; DNA-BINDING PROTEINS; FEMALE; GENOTYPE; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MALE; MOTOR NEURONS; MUTATION; OPEN READING FRAMES; PATCH-CLAMP TECHNIQUES; POTASSIUM; PROTEINS; SODIUM;

EID: 84923091694     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms6999     Document Type: Article

References (54)

1. Al-Chalabi, A. et al. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 124, 339-352 (2012).
2. Renton, A. E., Chiò, A. & Traynor, B. J. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17-23 (2014).
3. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133 (2006).
4. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672 (2008).
5. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245-256 (2011).
6. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268 (2011).
7. Benatar, M. Lost in translation: Treatment trials in the SOD1 mouse and in human ALS. Neurobiol. Dis. 26, 1-13 (2007).
8. Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221 (2008).
9. Bilican, B. et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc. Natl Acad. Sci. USA 109, 5803-5808 (2012).
10. Egawa, N. et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci. Transl. Med. 4, 145ra104-145ra104 (2012).
11. Donnelly, C. J. et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80, 415-428 (2013).
12. Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci. Transl. Med. 5, 208ra149 (2013).
13. Zhang, Z. et al. Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS ONE 8, e76055 (2013).
14. Wainger, B. J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 1-11 (2014).
15. Kiskinis, E. et al. Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell 14, 781-795 (2014).
16. Kuo, J. J., Siddique, T., Fu, R. & Heckman, C. J. Increased persistent Na(\+) current and its effect on excitability in motoneurones cultured from mutant SOD1 mice. J. Physiol. 563, 843-854 (2005).
17. Zona, C., Pieri, M. & Carunchio, I. Voltage-dependent sodium channels in spinal cord motor neurons display rapid recovery from fast inactivation in a mouse model of amyotrophic lateral sclerosis. J. Neurophysiol. 96, 3314-3322 (2006).
18. Bories, C., Amendola, J., Lamotte d'Incamps, B. & Durand, J. Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 25, 451-459 (2007).
19. Pieri, M. et al. Altered excitability of motor neurons in a transgenic mouse model of familial amyotrophic lateral sclerosis. Neurosci. Lett. 351, 153-156 (2003).
20. Van Zundert, B. et al. Disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J. Neurosci. 28, 10864-10874 (2008).
21. Quinlan, K. A., Schuster, J. E., Fu, R., Siddique, T. & Heckman, C. J. Altered postnatal maturation of electrical properties in spinal motoneurons in a mouse model of amyotrophic lateral sclerosis. J. Physiol. 589, 2245-2260 (2011).
22. Fuchs, A. et al. Selective mitochondrial Ca2\+ uptake deficit in disease endstage vulnerable motoneurons of the SOD1G93A mouse model of amyotrophic lateral sclerosis. J. Physiol. 591, 2723-2745 (2013).
23. Kanai, K. et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 129, 953-962 (2006).
24. Vucic, S., Nicholson, G. A. & Kiernan, M. C. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131, 1540-1550 (2008).
25. Yusa, K. et al. Targeted gene correction of a1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478, 391-394 (2011).
26. Amoroso, M. W. et al. Accelerated high-yield generation of limb-innervating motor neurons from human stem cells. J. Neurosci. 33, 574-586 (2013).
27. Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761-772 (2009).
28. Matsumoto, S., Goto, S., Kusaka, H., Ito, H. & Imai, T. Synaptic pathology of spinal anterior horn cells in amyotrophic lateral sclerosis: An immunohistochemical study. J. Neurol. Sci. 125, 180-185 (1994).
29. Sasaki, S. & Maruyama, S. Synapse loss in anterior horn neurons in amyotrophic lateral sclerosis. Acta Neuropathol. 88, 222-227 (1994).
30. Ince, P. G. et al. Quantitative study of synaptophysin immunoreactivity of cerebral cortex and spinal cord in motor neuron disease. J. Neuropathol. Exp. Neurol. 54, 673-679 (1995).
31. Jiang, M., Schuster, J. E., Fu, R., Siddique, T. & Heckman, C. J. Progressive changes in synaptic inputs to motoneurons in adult sacral spinal cord of a mouse model of amyotrophic lateral sclerosis. J. Neurosci. 29, 15031-15038 (2009).
32. Chang, Q. & Martin, L. J. Glycinergic innervation of motoneurons is deficient in amyotrophic lateral sclerosis mice: a quantitative confocal analysis. Am. J. Pathol. 174, 574-585 (2009).
33. Schutz, B. Imbalanced excitatory to inhibitory synaptic input precedes motor neuron degeneration in an animal model of amyotrophic lateral sclerosis. Neurobiol. Dis. 20, 131-140 (2005).
34. Almeida, S. et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 126, 385-399 (2013).
35. Mitne-Neto, M. et al. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Hum. Mol. Genet. 20, 3642-3652 (2011).
36. Vucic, S. & Kiernan, M. C. Axonal excitability properties in amyotrophic lateral sclerosis. Clin. Neurophysiol. 117, 1458-1466 (2006).
37. Delestreé, N. et al. Adult spinal motoneurones are not hyperexcitable in a mouse model of inherited amyotrophic lateral sclerosis. J. Physiol. 592, 1687-1703 (2014).
38. Von Lewinski, F., Fuchs, J., Vanselow, B. K. & Keller, B. U. Low Ca2\+ buffering in hypoglossal motoneurons of mutant SOD1 (G93A) mice. Neurosci. Lett. 445, 224-228 (2008).
39. Jaiswal, M. K. & Keller, B. U. Cu/Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of mitochondria and perturbs Ca2\+ homeostasis in SOD1G93A mice. Mol. Pharmacol. 75, 478-489 (2009).
40. Saxena, S. et al. Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. Neuron 80, 80-96 (2013).
41. Zagoraiou, L. et al. Article a cluster of cholinergic premotor interneurons modulates mouse locomotor activity. Neuron 64, 645-662 (2009).
42. Miles, G. B., Hartley, R., Todd, A. J. & Brownstone, R. M. Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion. Proc. Natl Acad. Sci. USA 104, 2448-2453 (2007).
43. Herron, L. R. & Miles, G. B. Gender-specific perturbations in modulatory inputs to motoneurons in a mouse model of amyotrophic lateral sclerosis. Neuroscience 226, 313-323 (2012).
44. Pullen, A. H. & Athanasiou, D. Increase in presynaptic territory of C-terminals on lumbar motoneurons of G93A SOD1 mice during disease progression. Eur. J. Neurosci. 29, 551-561 (2009).
45. Pieri, M., Carunchio, I., Curcio, L., Mercuri, N. B. & Zona, C. Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis. Exp. Neurol. 215, 368-379 (2009).
46. Bostock, H., Sharief, M. K., Reid, G. & Murray, N. M. Axonal ion channel dysfunction in amyotrophic lateral sclerosis. Brain 118(Pt 1): 217-225 (1995).
47. Tamura, N. et al. Increased nodal persistent Na\+ currents in human neuropathy and motor neuron disease estimated by latent addition. Clin. Neurophysiol. 117, 2451-2458 (2006).
48. Israelson, A. et al. Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron 67, 575-587 (2010).
49. Ellis, D., Rabe, J. & Sweadner, K. Global loss of Na,K-ATPase and its nitric oxide-mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis. J. Neurosci. 23, 43-51 (2003).
50. Arnold, E. S. et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc. Natl Acad. Sci. USA 110, E736-E745 (2013).
51. Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452-458 (2011).
52. Alami, N. H. et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81, 536-543 (2014).
53. Lagier-Tourenne, C. et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat. Neurosci. 15, 1488-1497 (2012).
54. Xu, Y.-F. et al. Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol. Neurodegener. 6, 73 (2011).