Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

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The term “motor neuron disease” refers to a group of disorders, causing progressive paralysis of affected patients due to the degeneration of motor neurons cells which control voluntary movements. Importantly, not all motor neurons appear to be affected in the same way, with those that control the face being affected less that those that control the abdomen. The reason why some motor neurons are more vulnerable is unknown; however, understanding this may provide new targets for therapeutics to slow motor neuron degeneration either as stand-alone therapeutics or in combination with SMN-inducing compounds. In this study, we analysed gene expression in different groups of motor neurons and compared this to previously published expression data to identify commonalities. One of the common transcripts was alpha-synuclein (SNCA), which was consistently expressed at lower levels in vulnerable motor neurons. Importantly, when SNCA levels were increased in a mouse model of motor neuron disease, the disease phenotype was significantly reduced, including an extension in survival and reduction in motor neuron pathology. Collectively, these results demonstrate that this approach can identify disease modifiers that can reduce disease severity in models of motor neuron disease and potentially identify new therapeutic targets.

Vyšlo v časopise: Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases. PLoS Genet 13(3): e32767. doi:10.1371/journal.pgen.1006680
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1006680

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Zdroje

1. Dion PA, Daoud H, Rouleau GA. Genetics of motor neuron disorders: new insights into pathogenic mechanisms. Nat Rev Genet. 2009;10(11):769–82. doi: 10.1038/nrg2680 19823194

2. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–65. 7813012

3. Rodrigues NR, Owen N, Talbot K, Ignatius J, Dubowitz V, Davies KE. Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. Hum Mol Genet. 1995;4(4):631–4. 7633412

4. Gavrilov DK, Shi X, Das K, Gilliam TC, Wang CH. Differential SMN2 expression associated with SMA severity. Nat Genet. 1998;20(3):230–1. doi: 10.1038/3030 9806538

5. La Spada A. Spinal and Bulbar Muscular Atrophy. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.

6. Comley LH, Nijssen J, Frost-Nylen J, Hedlund E. Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology. J Comp Neurol. 2016;524(7):1424–42. doi: 10.1002/cne.23917 26502195

7. Ling KK, Gibbs RM, Feng Z, Ko CP. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy. Hum Mol Genet. 2012;21(1):185–95. doi: 10.1093/hmg/ddr453 21968514

8. Murray LM, Beauvais A, Bhanot K, Kothary R. Defects in neuromuscular junction remodelling in the Smn(2B/-) mouse model of spinal muscular atrophy. Neurobiol Dis. 2013;49:57–67. doi: 10.1016/j.nbd.2012.08.019 22960106

9. Murray LM, Comley LH, Thomson D, Parkinson N, Talbot K, Gillingwater TH. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum Mol Genet. 2008;17(7):949–62. doi: 10.1093/hmg/ddm367 18065780

10. Deymeer F, Serdaroglu P, Parman Y, Poda M. Natural history of SMA IIIb: muscle strength decreases in a predictable sequence and magnitude. Neurology. 2008;71(9):644–9. doi: 10.1212/01.wnl.0000324623.89105.c4 18725590

11. Kubota M, Sakakihara Y, Uchiyama Y, Nara A, Nagata T, Nitta H, et al. New ocular movement detector system as a communication tool in ventilator-assisted Werdnig-Hoffmann disease. Dev Med Child Neurol. 2000;42(1):61–4. 10665977

12. Gizzi M, DiRocco A, Sivak M, Cohen B. Ocular motor function in motor neuron disease. Neurology. 1992;42(5):1037–46. 1579227

13. Haenggeli C, Kato AC. Differential vulnerability of cranial motoneurons in mouse models with motor neuron degeneration. Neurosci Lett. 2002;335(1):39–43. 12457737

14. Nimchinsky EA, Young WG, Yeung G, Shah RA, Gordon JW, Bloom FE, et al. Differential vulnerability of oculomotor, facial, and hypoglossal nuclei in G86R superoxide dismutase transgenic mice. J Comp Neurol. 2000;416(1):112–25. 10578106

15. Achsel T, Barabino S, Cozzolino M, Carri MT. The intriguing case of motor neuron disease: ALS and SMA come closer. Biochem Soc Trans. 2013;41(6):1593–7. doi: 10.1042/BST20130142 24256260

16. Murray LM, Beauvais A, Gibeault S, Courtney NL, Kothary R. Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn (2b/-) mouse model of spinal muscular atrophy. Acta Neuropathol Commun. 2015;3:55. doi: 10.1186/s40478-015-0231-1 26374403

17. Brockington A, Ning K, Heath PR, Wood E, Kirby J, Fusi N, et al. Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathol. 2013;125(1):95–109. doi: 10.1007/s00401-012-1058-5 23143228

18. Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O. Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection. Brain. 2010;133(Pt 8):2313–30. doi: 10.1093/brain/awq167 20826431

19. Kaplan A, Spiller KJ, Towne C, Kanning KC, Choe GT, Geber A, et al. Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron. 2014;81(2):333–48. doi: 10.1016/j.neuron.2013.12.009 24462097

20. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004;75(5):822–31. doi: 10.1086/425287 15372378

21. Chen HJ, Anagnostou G, Chai A, Withers J, Morris A, Adhikaree J, et al. Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J Biol Chem. 2010;285(51):40266–81. doi: 10.1074/jbc.M110.161398 20940299

22. Larroquette F, Seto L, Gaub PL, Kamal B, Wallis D, Lariviere R, et al. Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response. Hum Mol Genet. 2015;24(22):6515–29. doi: 10.1093/hmg/ddv360 26362257

23. Sanhueza M, Chai A, Smith C, McCray BA, Simpson TI, Taylor JP, et al. Network analyses reveal novel aspects of ALS pathogenesis. PLoS Genet. 2015;11(3):e1005107. doi: 10.1371/journal.pgen.1005107 25826266

24. Peretti D, Dahan N, Shimoni E, Hirschberg K, Lev S. Coordinated lipid transfer between the endoplasmic reticulum and the Golgi complex requires the VAP proteins and is essential for Golgi-mediated transport. Mol Biol Cell. 2008;19(9):3871–84. doi: 10.1091/mbc.E08-05-0498 18614794

25. Gomez-Suaga P, Paillusson S, Stoica R, Noble W, Hanger DP, Miller CC. The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy. Curr Biol. 2017;27(3):371–85. doi: 10.1016/j.cub.2016.12.038 28132811

26. Han SM, El Oussini H, Scekic-Zahirovic J, Vibbert J, Cottee P, Prasain JK, et al. VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans. PLoS Genet. 2013;9(9):e1003738. doi: 10.1371/journal.pgen.1003738 24039594

27. Perrimon N, Noll E, Mccall K, Brand A. Generating Lineage-Specific Markers to Study Drosophila Development. Dev Genet. 1991;12(3):238–52. doi: 10.1002/dvg.1020120309 1651183

28. Forrest S, Chai A, Sanhueza M, Marescotti M, Parry K, Georgiev A, et al. Increased levels of phosphoinositides cause neurodegeneration in a Drosophila model of amyotrophic lateral sclerosis. Hum Mol Genet. 2013;22(13):2689–704. doi: 10.1093/hmg/ddt118 23492670

29. Acsadi G, Li X, Murphy KJ, Swoboda KJ, Parker GC. Alpha-synuclein loss in spinal muscular atrophy. J Mol Neurosci. 2011;43(3):275–83. doi: 10.1007/s12031-010-9422-1 20640532

30. da Costa CA, Ancolio K, Checler F. Wild-type but not Parkinson's disease-related ala-53 —> Thr mutant alpha -synuclein protects neuronal cells from apoptotic stimuli. J Biol Chem. 2000;275(31):24065–9. doi: 10.1074/jbc.M002413200 10818098

31. Hashimoto M, Hsu LJ, Rockenstein E, Takenouchi T, Mallory M, Masliah E. alpha-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. J Biol Chem. 2002;277(13):11465–72. doi: 10.1074/jbc.M111428200 11790792

32. Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA. Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci. 2003;23(8):3095–9. 12716914

33. Zhou W, Hurlbert MS, Schaack J, Prasad KN, Freed CR. Overexpression of human alpha-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells. Brain Res. 2000;866(1–2):33–43. 10825478

34. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009;27(1):59–65. doi: 10.1038/nbt.1515 19098898

35. Robbins KL, Glascock JJ, Osman EY, Miller MR, Lorson CL. Defining the therapeutic window in a severe animal model of spinal muscular atrophy. Hum Mol Genet. 2014;23(17):4559–68. doi: 10.1093/hmg/ddu169 24722206

36. Butchbach ME. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front Mol Biosci. 2016;3:7. doi: 10.3389/fmolb.2016.00007 27014701

37. Ladd AN, Charlet N, Cooper TA. The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol Cell Biol. 2001;21(4):1285–96. doi: 10.1128/MCB.21.4.1285-1296.2001 11158314

38. Qin Y, Chen Z, Han X, Wu H, Yu Y, Wu J, et al. Progesterone attenuates Abeta(25–35)-induced neuronal toxicity via JNK inactivation and progesterone receptor membrane component 1-dependent inhibition of mitochondrial apoptotic pathway. J Steroid Biochem Mol Biol. 2015;154:302–11. doi: 10.1016/j.jsbmb.2015.01.002 25576906

39. Jackson AC, Roche SL, Byrne AM, Ruiz-Lopez AM, Cotter TG. Progesterone receptor signalling in retinal photoreceptor neuroprotection. J Neurochem. 2016;136(1):63–77. doi: 10.1111/jnc.13388 26447367

40. Rubin CI, Atweh GF. The role of stathmin in the regulation of the cell cycle. J Cell Biochem. 2004;93(2):242–50. doi: 10.1002/jcb.20187 15368352

41. Liedtke W, Leman EE, Fyffe RE, Raine CS, Schubart UK. Stathmin-deficient mice develop an age-dependent axonopathy of the central and peripheral nervous systems. Am J Pathol. 2002;160(2):469–80. doi: 10.1016/S0002-9440(10)64866-3 11839567

42. Strey CW, Spellman D, Stieber A, Gonatas JO, Wang X, Lambris JD, et al. Dysregulation of stathmin, a microtubule-destabilizing protein, and up-regulation of Hsp25, Hsp27, and the antioxidant peroxiredoxin 6 in a mouse model of familial amyotrophic lateral sclerosis. Am J Pathol. 2004;165(5):1701–18. doi: 10.1016/S0002-9440(10)63426-8 15509539

43. Wen HL, Ting CH, Liu HC, Li H, Lin-Chao S. Decreased stathmin expression ameliorates neuromuscular defects but fails to prolong survival in a mouse model of spinal muscular atrophy. Neurobiol Dis. 2013;52:94–103. doi: 10.1016/j.nbd.2012.11.015 23268200

44. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997;276(5321):2045–7. 9197268

45. Maroteaux L, Campanelli JT, Scheller RH. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci. 1988;8(8):2804–15. 3411354

46. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, et al. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010;65(1):66–79. doi: 10.1016/j.neuron.2009.12.023 20152114

47. Yavich L, Tanila H, Vepsalainen S, Jakala P. Role of alpha-synuclein in presynaptic dopamine recruitment. J Neurosci. 2004;24(49):11165–70. doi: 10.1523/JNEUROSCI.2559-04.2004 15590933

48. Glascock JJ, Shababi M, Wetz MJ, Krogman MM, Lorson CL. Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of spinal muscular atrophy. Biochem Biophys Res Commun. 2012;417(1):376–81. doi: 10.1016/j.bbrc.2011.11.121 22172949

49. Shababi M, Glascock J, Lorson CL. Combination of SMN trans-splicing and a neurotrophic factor increases the life span and body mass in a severe model of spinal muscular atrophy. Hum Gene Ther. 2011;22(2):135–44. doi: 10.1089/hum.2010.114 20804424