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New Approaches in Studies of the Molecular Pathogenesis of Type 2 Spinocerebellar Ataxia

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Type 2 spinocerebellar ataxia (SCA2) is an inherited progressive disease whose cause at the genetic level is an expansion of the polyglutamine tract in ataxin-2 protein. Effective treatment and disease-modifying therapy remain unavailable to patients with SCA2. Patients are currently given only symptomatic treatment, along with palliative medical care. With the aim of seeking new therapeutic targets for treatment of SCA2, many scientific groups have tried to study the physiological, molecular, and biochemical changes to cerebellar neurons in patients with SCA2 and in various model systems. State-of-the-art approaches to studies of the pathogenesis of SCA2 have yielded new data on the molecular mechanisms of the disease and have suggested possible strategies for the potential treatment of this disease. The present review summarizes current data on the genetic basis of SCA2, describes the known properties and functions of ataxin-2 protein, considers the mechanisms of degeneration of cerebellar cortex cells, impairments to their physiological function, and associated damage to the conducting pathways of the cerebellum, and presents data on contemporary model systems used for studies of the basis of SCA2; we also present information on novel approaches to studies of the molecular mechanisms underlying the pathology of SCA2 such as aggregation, oxidative stress, and damage to cell signaling and calcium signaling, and consider the role of autophagy and the microglia in the molecular pathogenesis of SCA2.

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References

  1. T. Ashizawa, G. Oz, and H. L. Paulson, “Spinocerebellar ataxias: Prospects and challenges for therapy development,” Nat. Dev. Neurol., 14, No. 10, 590–605 (2018).

    Google Scholar 

  2. J. J. Magana, L. Velazquez-Perez, and B. Cisneros, “Spinocerebellar ataxia type 2: Clinical presentation, molecular mechanisms, and therapeutic perspectives,” Mol. Neurobiol., 47, No. 1, 90–104 (2013).

    CAS  PubMed  Google Scholar 

  3. H. L. Paulson, V. G. Shakkottai, H. B. Clark, and H. T. Orr, “Polyglutamine spinocerebellar ataxias – from genes to potential treatments,” Nat. Rev. Neurosci., 18, No. 10, 613–626 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. D. R. Scoles and S. M. Pulst, “Spinocerebellar ataxia type 2,” Adv. Exp. Med. Biol., 1049, 175–195 (2018).

    CAS  PubMed  Google Scholar 

  5. R. A. M. Buijsen, L. J. A. Toonen, S. L. Gardiner, and W. M. C. van Roon-Mom, “Genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias,” Neurotherapeutics, (2019).

  6. T. F. Satterfield and L. J. Pallanck, “Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes,” Hum. Mol. Genet., 15, No. 16, 2523–2532 (2006).

    CAS  PubMed  Google Scholar 

  7. J. M. Alves-Cruzeiro, L. Mendonca, L. Pereira de Almeida, and C. Nobrega, “Motor dysfunctions and neuropathology in mouse models of spinocerebellar ataxia type 2: A comprehensive review,” Front. Neurosci., 10, 572 (2016).

    PubMed  PubMed Central  Google Scholar 

  8. C. J. Smeets and D. S. Verbeek, “Climbing fi bers in spinocerebellar ataxia: A mechanism for the loss of motor control,” Neurobiol. Dis., 88, 96–106 (2016).

    CAS  PubMed  Google Scholar 

  9. T. Takeuchi and Y. Nagai, “Protein misfolding and aggregation as a therapeutic target for polyglutamine diseases,” Brain Sci., 7, No. 10 (2017).

  10. T. H. Massey and L. Jones, “The central role of DNA damage and repair in CAG repeat diseases,” Dis. Model Mech., 11, No. 1 (2018).

  11. P. Egorova, E. Popugaeva, and I. Bezprozvanny, “Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer’s disease,” Semin. Cell. Dev. Biol., 40, 127–133 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. P. A. Egorova and I. B. Bezprozvanny, “Inositol-1,4,5-trisphosphate receptors and neurodegenerative disorders,” FEBS J., 285, No. 19, 3547–3565 (2018).

    CAS  PubMed  Google Scholar 

  13. C. Hisatsune, K. Hamada, and K. Mikoshiba, “Ca(2+) signaling and spinocerebellar ataxia,” Biochem. Biophys. Acta Mol. Cell. Res., 11, 1733–1744 (2018).

    Google Scholar 

  14. M. D. Mark, J. C. Schwitalla, M. Groemmke, and S. Herlitze, “Keeping our calcium in balance to maintain our balance,” Biochem. Biophys. Res. Commun, 483, No. 4, 1040–1050 (2017).

    CAS  PubMed  Google Scholar 

  15. A. Ashkenazi, C. F. Bento, T. Ricketts, et al., “Polyglutamine tracts regulate autophagy,” Autophagy, 13, No. 9, 1613–1614 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. W. Y. Yau, E. O’Connor, R. Sullivan, et al., “DNA repair in trinucleotide repeat ataxias,” FEBS J., 285, No. 19, 3669–3682 (2018).

    CAS  PubMed  Google Scholar 

  17. D. R. Scoles, P. Meera, M. D. Schneider, et al., “Antisense oligonucleotide therapy for spinocerebellar ataxia type 2,” Nature, 544, No. 7650, 362–366 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. H. A. G. Teive, C. H. F. Camargo, and R. P. Munhoz, “Antisense oligonucleotide therapy for spinocerebellar ataxias: Good news for terrible diseases,” Mov. Disord. Clin. Pract., 5, 4, 400–403 (2018).

    Google Scholar 

  19. Y. A. Tsai, R. S. Liu, J. F. Lirng, et al., “Treatment of spinocerebellar ataxia with mesenchymal stem cells: A Phase I/IIa Clinical Study,” Cell Transplant., 26, No. 3, 503–512 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. S. Romano, G. Coarelli, C. Marcotulli, et al., “Riluzole in patients with hereditary cerebellar ataxia: A randomised, double-blind, placebo- controlled trial,” Lancet Neurol., 14, No. 10, 985–991 (2015).

    CAS  PubMed  Google Scholar 

  21. J. Liu, T. S. Tang, H. Tu, et al., “Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2,” J. Neurosci., 29, No. 29, 9148–9162 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. A. W. Kasumu, X. Liang, P. Egorova, et al., “Chronic suppression of inositol 1,4,5-triphosphate receptor-mediated calcium signaling in cerebellar Purkinje cells alleviates pathological phenotype in spinocerebellar ataxia 2 mice,” J. Neurosci., 32, No. 37, 12786–12796 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. D. D. Bushart, R. Chopra, V. Singh, et al., “Targeting potassium channels to treat cerebellar ataxia,” Ann. Clin. Transl. Neurol., 5, No. 3, 297–314 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. S. Gispert, R. Twells, G. Orozco, et al., “Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1,” Nat. Genet., 4, No. 3, 295–299 (1993).

    CAS  PubMed  Google Scholar 

  25. M. Fernandez, M. E. McClain, R. A. Martinez, et al., “Late-onset SCA2: 33 CAG repeats are suffi cient to cause disease,” Neurology, 55, No. 4, 569–572 (2000).

    CAS  PubMed  Google Scholar 

  26. S. M. Pulst, “The complex structure of ATXN2 genetic variation,” Neurol. Genet., 4, No. 6, e299 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. L. E. Almaguer-Mederos, J. M. L. Mesa, Y. Gonzalez-Zaldivar, et al., “Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in spinocerebellar ataxia type 2,” Clin. Genet., 94, No. 3–4, 346–350 (2018).

    CAS  PubMed  Google Scholar 

  28. L. S. Sena, R. M. Castilhos, E. P. Mattos, et al., “Selective forces related to spinocerebellar ataxia type 2,” Cerebellum, 18, No. 2, 188–194 (2019).

    CAS  PubMed  Google Scholar 

  29. S. van de Loo, F. Eich, D. Nonis, et al., “Ataxin-2 associates with rough endoplasmic reticulum,” Exp. Neurol., 215, No. 1, 110–118 (2009).

    PubMed  Google Scholar 

  30. T. R. Kiehl, A. Nechiporuk, K. P. Figueroa, et al., “Generation and characterization of Sca2 (ataxin-2) knockout mice,” Biochem. Biophys. Res. Commun, 339, No. 1, 17–24 (2006).

    CAS  PubMed  Google Scholar 

  31. I. Lastres-Becker, S. Brodesser, D. Lutjohann, et al., “Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice,” Hum. Mol. Genet., 17, No. 10, 1465–1481 (2008).

    CAS  PubMed  Google Scholar 

  32. M. Pfeffer, S. Gispert, G. Auburger, et al., “Impact of ataxin-2 knock out on circadian locomotor behavior and PER immunoreaction in the SCN of mice,” Chronobiol. Int., 34, No. 1, 129–137 (2017).

    CAS  PubMed  Google Scholar 

  33. C. Lim and R. Allada, “ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila,” Science, 340, No. 6134, 875–879 (2013).

    CAS  PubMed  Google Scholar 

  34. Y. Zhang, J. Ling, C. Yuan, et al., “A role for Drosophila ATX2 in activation of PER translation and circadian behavior,” Science, 340, No. 6134, 879–882 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. K. Seidel, S. Siswanto, M. Fredrich, et al., “On the distribution of intranuclear and cytoplasmic aggregates in the brainstem of patients with spinocerebellar ataxia type 2 and 3,” Brain Pathol., 27, No. 3, 345–355 (2017).

    CAS  PubMed  Google Scholar 

  36. N. S. Lim, G. Kozlov, T. C. Chang, et al., “Comparative peptide binding studies of the PABC domains from the ubiquitin-protein isopeptide ligase HYD and poly(A)-binding protein. Implications for HYD function,” J. Biol. Chem., 281, No. 20, 14,376–14,382 (2006).

    CAS  Google Scholar 

  37. I. Lastres-Becker, D. Nonis, F. Eich, et al., “Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/ mTOR and is induced by starvation,” Biochim. Biophys. Acta, 1862, No. 9, 1558–1569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. U. Nonhoff, M. Ralser, F. Welzel, et al., “Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules,” Mol. Biol. Cell., 18, No. 4, 1385–1396 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. B. Bakthavachalu, J. Huelsmeier, I. P. Sudhakaran, et al., “RNPgranule assembly via ataxin-2 disordered domains is required for long-term memory and neurodegeneration,” Neuron, 98, No. 4, 754– 766 e4 (2018).

    CAS  PubMed  Google Scholar 

  40. L. A. Ostrowski, A. C. Hall, K. J. Szafranski, et al., “Conserved Pbp1/Ataxin-2 regulates retrotransposon activity and connects polyglutamine expansion-driven protein aggregation to lifespan-controlling rDNA repeats,” Commun. Biol., 1, 187 (2018).

    PubMed  PubMed Central  Google Scholar 

  41. N. E. Sen, J. Drost, S. Gispert, et al., “Search for SCA2 blood RNA biomarkers highlights Ataxin-2 as strong modifi er of the mitochondrial factor PINK1 levels,” Neurobiol. Dis., 96, 115–126 (2016).

    CAS  PubMed  Google Scholar 

  42. P. P. Li, X. Sun, G. Xia, et al., “ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis,” Ann. Neurol., 80, No. 4, 600–615 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. M. Fittschen, I. Lastres-Becker, M. V. Halbach, et al., “Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate,” Neurogenetics, 16, No. 3, 181–192 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. D. Meierhofer, M. Halbach, N. E. Sen, et al., “Ataxin-2 (Atxn2)- knock-out mice show branched chain amino acids and fatty acids pathway alterations,” Mol. Cell. Proteomics, 15, No. 5, 1728–39 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. M. V. Halbach, S. Gispert, T. Stehning, et al., “Atxn2 Knockout and CAG42-knock-in cerebellum shows similarly dysregulated expression in calcium homeostasis pathway,” Cerebellum, 16, No. 1, 68–81 (2017).

    CAS  PubMed  Google Scholar 

  46. E. D. Louis, S. H. Kuo, W. J. Tate, et al., “Heterotopic Purkinje cells: a comparative postmortem study of essential tremor and spinocerebellar ataxias 1, 2, 3, and 6,” Cerebellum, 17, No. 2, 104–110 (2018).

    PubMed  PubMed Central  Google Scholar 

  47. E. A. R. Nibbeling, A. Duarri, C. C. Verschuuren-Bemelmans, et al., “Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia,” Brain, 140, No. 11, 2860– 2878 (2017).

    PubMed  Google Scholar 

  48. B. E. Aboulhoda and S. S. Hassan, “Effect of prenatal tramadol on postnatal cerebellar development: Role of oxidative stress,” J. Chem. Neuroanat., 94, 102–118 (2018).

    CAS  PubMed  Google Scholar 

  49. S. Squadrone, P. Brizio, C. Mancini, et al., “Altered homeostasis of trace elements in the blood of SCA2 patients,” J. Trace Elem. Med. Biol., 47, 111–114 (2018).

    CAS  PubMed  Google Scholar 

  50. M. Guevara-Garcia, L. Gil-del Valle, L. Velasquez-Perez, and J. C. Garcia-Rodriguez, “Oxidative stress as a cofactor in spinocerebellar ataxia type 2,” Redox Rep., 17, No. 2, 84–89 (2012).

    CAS  PubMed  Google Scholar 

  51. D. Almaguer-Gotay, L. E. Almaguer-Mederos, R. Aguilera-Rodriguez, et al., “Spinocerebellar ataxia type 2 is associated with the extracellular loss of superoxide dismutase but not catalase activity,” Front. Neurol., 8, 276 (2017).

    PubMed  PubMed Central  Google Scholar 

  52. L. E. Almaguer-Mederos, D. Almaguer-Gotay, R. Aguilera-Rodriguez, et al., “Association of glutathione S-transferase omega polymorphism and spinocerebellar ataxia type 2,” J. Neurol. Sci, 372, 324–328 (2017).

    CAS  PubMed  Google Scholar 

  53. T. L. Monte, F. S. Pereira, E. D. R. Reckziegel, et al., “Neurological phenotypes in spinocerebellar ataxia type 2: Role of mitochondrial polymorphism A10398G and other risk factors,” Parkinsonism Relat. Disord., 42, 54–60 (2017).

    PubMed  Google Scholar 

  54. H. Hamzeiy, D. Savas, C. Tunca, et al., “Elevated global DNA methylation is not exclusive to amyotrophic lateral sclerosis and is also observed in spinocerebellar ataxia types 1 and 2,” Neurodeg. Dis., 18, No. 1, 38–48 (2018).

    CAS  Google Scholar 

  55. C. Wilke, F. Bender, S. N. Hayer, et al., “Serum neurofi lament light is increased in multiple system atrophy of cerebellar type and in repeat- expansion spinocerebellar ataxias: A pilot study,” J. Neurol., 265, No. 7, 1618–1624 (2018).

    PubMed  Google Scholar 

  56. D. P. Huynh, K. Figueroa, N. Hoang, and S. M. Pulst, “Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human,” Nat. Genet., 26, No. 1, 44–50 (2000).

    CAS  PubMed  Google Scholar 

  57. A. W. Kasumu, C. Hougaard, F. Rode, et al., “Selective positive modulator of calcium-activated potassium channels exerts benefi cial effects in a mouse model of spinocerebellar ataxia type 2,” Chem. Biol., 19, No. 10, 1340–1353 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. P. A. Egorova, O. A. Zakharova, O. L. Vlasova, and I. B. Bezprozvanny, “In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model,” J. Neurophysiol., 115, No. 6, 2840–2851 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. P. A. Egorova, A. V. Gavrilova, and I. B. Bezprozvanny, “In vivo analysis of the climbing fiber-Purkinje cell circuit in SCA2-58Q transgenic mouse model,” Cerebellum, 17, No. 5, 590–600 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. J. Aguiar, J. Fernandez, A. Aguilar, et al., “Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specifi c Purkinje cell degeneration in transgenic mice,” Neurosci. Lett., 392, No. 3, 202–206 (2006).

    CAS  PubMed  Google Scholar 

  61. E. Damrath, M. V. Heck, S. Gispert, et al., “ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice,” PLoS Genetics, 8, No. 8, e1002920 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. S. T. Hansen, P. Meera, T. S. Otis, and S. M. Pulst, “Changes in Purkinje cell fi ring and gene expression precede behavioral pathology in a mouse model of SCA2,” Hum. Mol. Genet., 22, No. 2, 271– 283 (2013).

    CAS  PubMed  Google Scholar 

  63. L. T. Pflieger, W. Dansithong, S. Paul, et al., “Gene co-expression network analysis for identifying modules and functionally enriched pathways in SCA2,” Hum. Mol. Genet., 26, No. 16, 3069–3080 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. W. Dansithong, S. Paul, K. P. Figueroa, et al., “Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model,” PLoS Genetics, 11, No. 4, e1005182 (2015).

    PubMed  PubMed Central  Google Scholar 

  65. C. Y. Chuang, C. C. Yang, B. W. Soong, et al., “Modeling spinocerebellar ataxias 2 and 3 with iPSCs reveals a role for glutamate in disease pathology,” Sci. Rep., 9, No. 1, 1166 (2019).

    PubMed  PubMed Central  Google Scholar 

  66. A. G. Marthaler, B. Schmid, A. Tubsuwan, et al., “Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H196,” Stem Cell. Res., 16, No. 1, 199–201 (2016).

    CAS  PubMed  Google Scholar 

  67. J. A. Maguire, A. L. Gagne, P. Gonzalez-Alegre, et al., “Generation of spinocerebellar ataxia type 2 induced pluripotent stem cell lines, CHOPi002-A and CHOPi003-A, from patients with abnormal CAG repeats in the coding region of the ATXN2 gene,” Stem Cell. Res., 34, 101361 (2019).

    CAS  PubMed  Google Scholar 

  68. T. W. Todd and J. Lim, “Aggregation formation in the polyglutamine diseases: Protection at a cost?” Mol. Cells, 36, No. 3, 185–194 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. S. Koyano, S. Yagishita, Y. Kuroiwa, et al., “Neuropathological staging of spinocerebellar ataxia type 2 by semiquantitative 1C2-positive neuron typing. Nuclear translocation of cytoplasmic 1C2 underlies disease progression of spinocerebellar ataxia type 2,” Brain Pathol., 24, No. 6, 599–606 (2014).

    CAS  PubMed  Google Scholar 

  70. M. Ueda, S. Li, M. Itoh, et al., “Polyglutamine expansion disturbs the endoplasmic reticulum formation, leading to caspase-7 activation through Bax,” Biochem. Biophys. Res. Commun, 443, No. 4, 1232– 1238 (2014).

    CAS  PubMed  Google Scholar 

  71. N. Cornelius, J. H. Wardman, I. P. Hargreaves, et al., “Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fi broblasts: Effect of coenzyme Q10 supplementation on these parameters,” Mitochondrion, 34, 103–114 (2017).

    CAS  PubMed  Google Scholar 

  72. R. Y. Lo, K. P. Figueroa, S. M. Pulst, et al., “Coenzyme Q10 and spinocerebellar ataxias,” Mov. Disord., 30, No. 2, 214–220 (2015).

    CAS  PubMed  Google Scholar 

  73. A. S. Brown, P. Meera, B. Altindag, et al., “MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias,” Proc. Natl. Acad. Sci. USA, 115, No. 52, E12407–E12416 (2018).

    CAS  PubMed  Google Scholar 

  74. D. S. Verbeek, J. Goedhart, L. Bruinsma, et al., “PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling,” J. Cell Sci., 121, No. 14, 2339–2349 (2008).

    CAS  PubMed  Google Scholar 

  75. E. Shimobayashi and J. P. Kapfhammer, “Calcium signaling, PKC gamma, IP3R1 and CAR8 link spinocerebellar ataxias and Purkinje cell dendritic development,” Curr. Neuropharmacol., 16, No. 2, 151–159 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. R. Chopra, A. H. Wasserman, S. M. Pulst, et al., “Protein kinase C activity is a protective modifi er of Purkinje neuron degeneration in cerebellar ataxia,” Hum. Mol. Genet., 27, No. 8, 1396–1410 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. M. K. Meffert, J. M. Chang, B. J. Wiltgen, et al., “NF-kappa B functions in synaptic signaling and behavior,” Nat. Neurosci., 6, No. 10, 1072–1078 (2003).

    CAS  PubMed  Google Scholar 

  78. A. Ferro, W. Qu, A. Lukowicz, et al., “Inhibition of NF-kappaB signaling in IKKbetaF/F;LysM Cre mice causes motor deficits but does not alter pathogenesis of spinocerebellar ataxia type 1,” PLoS One, 13, No. 7, e0200013 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. Y. X. Li, O. C. M. Sibon, and P. F. Dijkers, “Inhibition of NF-kappaB in astrocytes is sufficient to delay neurodegeneration induced by proteotoxicity in neurons,” J. Neuroinflammation, 15, No. 1, 261 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. B. Alberts, Molecular Biology of the Cell, Garland Science, New York (2002), 4th ed.

  81. M. Huang and D. S. Verbeek, “Why do so many genetic insults lead to Purkinje cell degeneration and spinocerebellar ataxia?” Neurosci. Lett., 688, 49–57 (2019).

    CAS  PubMed  Google Scholar 

  82. B. Schwaller, M. Meyer, and S. Schiffmann, “’New’ functions for ‘old’ proteins: The role of the calcium-binding proteins calbindin D-28k, calretinin and parvalbumin, in cerebellar physiology. Studies with knockout mice,” Cerebellum, 1, No. 4, 241–258 (2002).

    CAS  PubMed  Google Scholar 

  83. L. Kreiner, C. J. Christel, M. Benveniste, et al., “Compensatory regulation of Cav2.1 Ca2+ channels in cerebellar Purkinje neurons lacking parvalbumin and calbindin D-28k,” J. Neurophysiol., 103, No. 1, 371–381 (2010).

    CAS  PubMed  Google Scholar 

  84. M. Kano, H. Nakayama, K. Hashimoto, et al., “Calcium-dependent regulation of climbing fi bre synapse elimination during postnatal cerebellar development,” J. Physiol., 591, No. 13, 3151–3158 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. J. A. Barnes, B. A. Ebner, L. A. Duvick, et al., “Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice,” J. Neurosci., 31, No. 36, 12778–12789 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. C. Long, C. E. Grueter, K. Song, et al., “Ataxia and Purkinje cell degeneration in mice lacking the C-AMTA1 transcription factor,” Proc. Natl. Acad. Sci. USA, 111, No. 31, 11521–11526 (2014).

    CAS  PubMed  Google Scholar 

  87. S. Y. Kawaguchi and T. Hirano, “Gating of long-term depression by Ca2+/calmodulin-dependent protein kinase II through enhanced cGMP signalling in cerebellar Purkinje cells,” J. Physiol., 591, No. 7, 1707– 1730 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. K. Fukumitsu, T. Hatsukano, A. Yoshimura, et al., “Mitochondrial fission protein Drp1 regulates mitochondrial transport and dendritic arborization in cerebellar Purkinje cells,” Mol. Cell. Neurosci., 71, 56–65 (2016).

    CAS  PubMed  Google Scholar 

  89. D. Di Bella, F. Lazzaro, A. Brusco, et al., “Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28,” Nat. Genet., 42, No. 4, 313–321 (2010).

    PubMed  Google Scholar 

  90. E. R. Kandel, Principles of Neural Science, A. L. H. Sydor (ed.), The McGraw-Hill Companies, USA (2013).

    Google Scholar 

  91. D. W. Indriati, N. Kamasawa, K. Matsui, et al., “Quantitative localization of Cav2.1 (P/Q-type) voltage-dependent calcium channels in Purkinje cells: Somatodendritic gradient and distinct somatic coclustering with calcium-activated potassium channels,” J. Neurosci., 33, No. 8, 3668–3678 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. C. Piochon, C. Levenes, G. Ohtsuki, and C. Hansel, “Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum,” J. Neurosci., 30, No. 45, 15,330–15,335 (2010).

    CAS  Google Scholar 

  93. R. Crupi, D. Impellizzeri, and S. Cuzzocrea, “Role of metabotropic glutamate receptors in neurological disorders,” Front. Mol. Neurosci., 12, 20 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. H. Hirai and M. Kano, “Type 1 metabotropic glutamate receptor and its signaling molecules as therapeutic targets for the treatment of cerebellar disorders,” Curr. Opin. Pharmacol., 38, 51–58 (2018).

    CAS  PubMed  Google Scholar 

  95. H. G. Serra, L. Duvick, T. Zu, et al., “RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice,” 127, No. 4, 697–708 (2006).

  96. D. A. Gold, S. H. Baek, N. J. Schork, et al., “RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways,” Neuron, 40, No. 6, 1119– 1131 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. H. T. Orr, “SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis,” Prog. Neurobiol., 99, No. 3, 179–185 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. P. Meera, S. Pulst, and T. Otis, “A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2,” eLife, 6 (2017).

  99. A. J. Collins, R. N. Foley, C. Herzog, et al., “US Renal Data System 2012 Ann Data Report,” Am. J. Kidney Dis., 61, No. 1, Suppl. 1, A7, e1-476 (2013).

  100. P. Meera, S. M. Pulst, and T. S. Otis, “Cellular and circuit mechanisms underlying spinocerebellar ataxias,” J. Physiol., 594, No. 16, 4653–4660 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. P. Grumati and I. Dikic, “Ubiquitin signaling and autophagy,” J. Biol. Chem., 293, No. 15, 5404–5413 (2018).

    CAS  PubMed  Google Scholar 

  102. N. Jatana, D. B. Ascher, D. E. V. Pires, et al., “Human LC3 and GABARAP subfamily members achieve functional specifi city via specifi c structural modulations,” Autophagy, 14, 1–17 (2019).

    Google Scholar 

  103. G. Puorro, A. Marsili, F. Sapone, et al., “Peripheral markers of autophagy in polyglutamine diseases,” Neurol. Sci., 39, No. 1, 149–152 (2018).

    PubMed  Google Scholar 

  104. S. Paul, W. Dansithong, K. P. Figueroa, et al., “Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration,” Nat. Commun., 9, No. 1, 3648 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. A. Ferro, C. Sheeler, J. G. Rosa, and M. Cvetanovic, “Role of microglia in ataxias,” J. Mol. Biol., (2019).

  106. M. S. Thion, D. Low, A. Silvin, et al., “Microbiome influences prenatal and adult microglia in a sex-specific manner,” Cell, 172, No. 3, 500–516 e16 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. H. Nakayama, M. Abe, C. Morimoto, et al., “Microglia permit climbing fi ber elimination by promoting GABAergic inhibition in the developing cerebellum,” Nat. Commun., 9, No. 1, 2830 (2018).

  108. B. A. Ebner, M. A. Ingram, J. A. Barnes, et al., “Purkinje cell ataxin- 1 modulates climbing fi ber synaptic input in developing and adult mouse cerebellum,” J. Neurosci., 33, No. 13, 5806–5820 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. M. Cvetanovic, M. Ingram, H. Orr, and P. Opal, “Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1,” Neuroscience, 289, 289–299 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. W. Qu, A. Johnson, J. H. Kim, et al., “Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice,” J. Neuroinflammation, 14, No. 1, 107 (2017).

  111. R. Llinas and M. Sugimori, “Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices,” J. Physiol., 305, 197–213 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. R. Llinas and M. Sugimori, “Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices,” J. Physiol., 305, 171–195 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. I. M. Raman and B. P. Bean, “Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons,” J. Neurosci., 17, No. 12, 4517–4526 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. I. M. Raman and B. P. Bean, “Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons,” J. Neurosci., 19, No. 5, 1663–1674 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. S. C. Nam and P. E. Hockberger, “Analysis of spontaneous electrical activity in cerebellar Purkinje cells acutely isolated from postnatal rats,” J. Neurobiol., 33, No. 1, 18–32 (1997).

    CAS  PubMed  Google Scholar 

  116. M. Womack and K. Khodakhah, “Active contribution of dendrites to the tonic and trimodal patterns of activity in cerebellar Purkinje neurons,” J. Neurosci., 22, No. 24, 10603–10612 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. S. L. Smith and T. S. Otis, “Persistent changes in spontaneous fi ring of Purkinje neurons triggered by the nitric oxide signaling caSCAde,” J. Neurosci., 23, No. 2, 367–372 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. C. I. De Zeeuw, F. E. Hoebeek, L. W. Bosman, et al., “Spatiotemporal firing patterns in the cerebellum,” Nat. Rev. Neurosci., 12, No. 6, 327–344 (2011).

    PubMed  Google Scholar 

  119. F. E. Hoebeek, J. S. Stahl, A. M. van Alphen, et al., “Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control,” Neuron, 45, No. 6, 953–965 (2005).

    CAS  PubMed  Google Scholar 

  120. K. Alvina and K. Khodakhah, “The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia,” J. Neurosci., 30, No. 21, 7258–7568 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. J. M. Dell’Orco, A. H. Wasserman, R. Chopra, et al., “Neuronal atrophy early in degenerative ataxia is a compensatory mechanism to regulate membrane excitability,” J. Neurosci., 35, No. 32, 11292– 11307 (2015).

    PubMed  PubMed Central  Google Scholar 

  122. M. D. Mark, M. Krause, H. J. Boele, et al., “Spinocerebellar ataxia type 6 protein aggregates cause defi cits in motor learning and cerebellar plasticity,” J. Neurosci., 35, No. 23, 8882–8895 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. V. G. Shakkottai, M. do Carmo Costa, J. M. Dell’Orco, et al., “Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3,” J. Neurosci., 31, No. 36, 13002–13014 (2011).

  124. J. T. Walter, K. Alvina, M. D. Womack, et al., “Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia,” Nat. Neurosci., 9, No. 3, 389–397 (2006).

    CAS  PubMed  Google Scholar 

  125. R. Chopra and V. G. Shakkottai, “Translating cerebellar Purkinje neuron physiology to progress in dominantly inherited ataxia,” Future Neurol., 9, No. 2, 187–196 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. J. M. Dell’Orco, S. M. Pulst, and V. G. Shakkottai, “Potassium channel dysfunction underlies Purkinje neuron spiking abnormalities in spinocerebellar ataxia type 2,” Hum. Mol. Genet., 26, No. 20, 3935– 3945 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. D. D. Bushart and V. G. Shakkottai, “Ion channel dysfunction in cerebellar ataxia,” Neurosci. Lett., 688, 41–48 (2019).

    CAS  PubMed  Google Scholar 

  128. M. Coutelier, G. Coarelli, M. L. Monin, et al., “A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies,” Brain, 140, No. 6, 1579–1594 (2017).

  129. J. M. Jones, L. Dionne, J. Dell’Orco, et al., “Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder,” Neurobiol. Dis., 89, 36–45 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. K. H. Lee, P. J. Mathews, A. M. Reeves, et al., “Circuit mechanisms underlying motor memory formation in the cerebellum,” Neuron, 86, No. 2, 529–540 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. E. J. Lang, R. Apps, F. Bengtsson, et al., “The roles of the olivocerebellar pathway in motor learning and motor control. A consensus paper,” Cerebellum, 16, No. 1, 230–252 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. S. H. Kuo, C. Y. Lin, J. Wang, et al., “Climbing fi ber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases,” Acta Neuropathol., 133, No. 1, 121–138 (2017).

    PubMed  Google Scholar 

  133. A. Burroughs, A. K. Wise, J. Xiao, et al., “The dynamic relationship between cerebellar Purkinje cell simple spikes and the spikelet number of complex spikes,” J. Physiol., 595, No. 1, 283–299 (2017).

    CAS  PubMed  Google Scholar 

  134. J. T. Davie, B. A. Clark, and M. Hausser, “The origin of the complex spike in cerebellar Purkinje cells,” J. Neurosci., 28, No. 30, 7599– 7609 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. T. V. Karelina and R. A. Grigor’ian, “Effect of harmaline of the complex spike waveform and depression time in cerebellar Purkinje cell discharge in rat postnatal ontogenesis,” Zh. Evol. Biokhim. Fiziol., 46, No. 3, 218–224 (2010).

    CAS  PubMed  Google Scholar 

  136. W. M. C. van Roon-Mom, R. A. C. Roos, and S. T. de Bot, “Dosedependent lowering of mutant huntingtin using antisense oligonucleotides in Huntington disease patients,” Nucleic Acid Ther., 28, No. 2, 59–62 (2018).

    PubMed  Google Scholar 

  137. C. Rinaldi and M. J. A. Wood, “Antisense oligonucleotides: The next frontier for treatment of neurological disorders,” Nat. Dev. Neurol., 14, No. 1, 9–21 (2018).

    CAS  Google Scholar 

  138. R. Volkman and D. Offen, “Concise review: mesenchymal stem cells in neurodegenerative diseases,” Stem Cells, 35, No. 8, 1867–1880 (2017).

    PubMed  Google Scholar 

  139. Y. K. Chang, M. H. Chen, Y. H. Chiang, et al., “Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells,” J. Biomed. Sci., 18, 54 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. L. T. Cho, A. J. Alexandrou, R. Torella, et al., “An Intracellular allosteric modulator binding pocket in SK2 ion channels is shared by multiple chemotypes,” Structure, 26, No. 4, 533-544 e3 (2018).

    CAS  PubMed  Google Scholar 

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  1. Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia

    P. A. Egorova & I. B. Bezprozvanny

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  1. P. A. Egorova
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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 105, No. 11, pp. 1349–1372, November, 2019.

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Egorova, P.A., Bezprozvanny, I.B. New Approaches in Studies of the Molecular Pathogenesis of Type 2 Spinocerebellar Ataxia. Neurosci Behav Physi 50, 938–951 (2020). https://doi.org/10.1007/s11055-020-00988-x

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  • DOI: https://doi.org/10.1007/s11055-020-00988-x

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