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Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

  • Polina A. Egorova
  • Ilya B. BezprozvannyEmail author
Review

Abstract

The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.

Key Words

Spinocerebellar ataxia type 2 polyglutamine disorders cerebellum calcium signaling aggregation. 

Abbreviations

ADCA

Autosomal dominant cerebellar ataxia

AP

Action potential

ASO

Antisense oligonucleotide

BAC

Bacterial artificial chromosome

BK channel

Large-conductance calcium-activated potassium channel

BN

Binucleated cell

Cdk5

Cyclin-dependent kinase 5

CF

Climbing fiber

CHIP

C-terminal constitutive Hsc70-interacting protein

CHZ

Chlorzoxazone

CS

Complex spike

DAG

Diacylglycerol

DTI

Diffusion-tensor imaging

EMG

Electromyography

EP

Evoked potential

ER

Endoplasmic reticulum

HD

Huntington’s disease

HSP

Heat shock protein

Htt

Huntingtin

IICR

IP3-induced calcium release

iPSCs

Induced pluripotent stem cells

IP3R

Inositol 1,4,5-trisphosphate receptor

KI

Knock-in

KO

Knockout

LTD

Long-term depression

MF

Mossy fiber

mGluR

Metabotropic glutamate receptor

MNi

Micronuclei formation

MRI

Magnetic resonance imaging

mRNA

Messenger RNA

MSCs

Mesenchymal stem cells

PABP

Poly(A)-binding protein

PC

Purkinje cell

Pcp2

Purkinje cell protein 2

PD

Parkinson’s disease

PF

Parallel fiber

PKC

Protein kinase C

PLM

Periodic leg movement

PolyQ

Polyglutamine

PTMs

Post-translational modifications

QBP1

PolyQ-binding protein 1

REM

Rapid eye movement

RORα

Retinoid-related orphan receptor α

RyR

Ryanodine receptor

SARA

Scale for the Assessment and Rating of Ataxia

SCA

Spinocerebellar ataxia

SCA2

Spinocerebellar ataxia type 2

SGs

Stress granules

SK channel

Small-conductance calcium-activated potassium channel

SOD

Superoxide dismutase

TRPC3

Transient receptor potential canonical 3

VBM

Voxel-based morphometry

VDCCs

Voltage-dependent calcium channels

WT

Wild type

5PP

IP3-phosphatase

Notes

Acknowledgments

Ilya B. Bezprozvanny is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer’s Disease Research. This work was supported by the National Institutes of Health Grant R01NS056224 (Ilya B. Bezprozvanny), Russian State Grant 17.991.2017/4.6 (Ilya B. Bezprozvanny), Russian Science Foundation Grant 18-75-00025 (Polina A. Egorova), Presidential Grant МК-1299.2019.4 (Polina A. Egorova), and Russian Science Foundation Grant 19-15-00184 (Ilya B. Bezprozvanny). The financial support was divided in the following way: research work related to Figure 1 was supported by the Russian State Grant 17.991.2017/4.6, research work related to Figure 2 was supported by the Presidential Grant МК-1299.2019.4, research work related to Figure 3 was supported by the Russian Science Foundation Grant 18-75-00025, and research work related to Figure 4 was supported by the Russian Science Foundation Grant 19-15-00184.

References

  1. 1.
    Ashizawa T, Oz G, Paulson HL. Spinocerebellar ataxias: prospects and challenges for therapy development. Nat Rev Neurol 2018;14(10):590–605.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Magana JJ, Velazquez-Perez L, Cisneros B. Spinocerebellar ataxia type 2: clinical presentation, molecular mechanisms, and therapeutic perspectives. Mol Neurobiol 2013;47(1):90–104.CrossRefPubMedGoogle Scholar
  3. 3.
    Paulson HL, Shakkottai VG, Clark HB, Orr HT. Polyglutamine spinocerebellar ataxias—from genes to potential treatments. Nat Rev Neurosci 2017;18(10):613–26.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Scoles DR, Pulst SM. Spinocerebellar ataxia type 2. Adv Exp Med Biol 2018;1049:175–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Buijsen RAM, Toonen LJA, Gardiner SL, van Roon-Mom WMC. Genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias. Neurotherapeutics. 2019.Google Scholar
  6. 6.
    Satterfield TF, Pallanck LJ. Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes. Hum Mol Genet 2006;15(16):2523–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Alves-Cruzeiro JM, Mendonca L, Pereira de Almeida L, Nobrega C. Motor dysfunctions and neuropathology in mouse models of spinocerebellar ataxia type 2: a comprehensive review. Front Neurosci. 2016;10:572.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Smeets CJ, Verbeek DS. Climbing fibers in spinocerebellar ataxia: a mechanism for the loss of motor control. Neurobiol Dis 2016;88:96–106.CrossRefPubMedGoogle Scholar
  9. 9.
    Takeuchi T, Nagai Y. Protein misfolding and aggregation as a therapeutic target for polyglutamine diseases. Brain Sci. 2017;7(10).Google Scholar
  10. 10.
    Massey TH, Jones L. The central role of DNA damage and repair in CAG repeat diseases. Dis Model Mech. 2018;11(1).Google Scholar
  11. 11.
    Egorova P, Popugaeva E, Bezprozvanny I. Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer’s disease. Semin Cell Dev Biol 2015;40:127–33.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Egorova PA, Bezprozvanny IB. Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders. FEBS J 2018;285(19):3547–65.CrossRefPubMedGoogle Scholar
  13. 13.
    Hisatsune C, Hamada K, Mikoshiba K. Ca(2+) signaling and spinocerebellar ataxia. Biochim Biophys Acta Mol Cell Res 2018.Google Scholar
  14. 14.
    Mark MD, Schwitalla JC, Groemmke M, Herlitze S. Keeping our calcium in balance to maintain our balance. Biochem Biophys Res Commun 2017;483(4):1040–50.CrossRefPubMedGoogle Scholar
  15. 15.
    Ashkenazi A, Bento CF, Ricketts T, et al. Polyglutamine tracts regulate autophagy. Autophagy. 2017;13(9):1613–4.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yau WY, O’Connor E, Sullivan R, Akijian L, Wood NW. DNA repair in trinucleotide repeat ataxias. FEBS J 2018;285(19):3669–82.CrossRefPubMedGoogle Scholar
  17. 17.
    Scoles DR, Meera P, Schneider MD, et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature. 2017;544(7650):362–6.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Teive HAG, Camargo CHF, Munhoz RP. Antisense oligonucleotide therapy for spinocerebellar ataxias: good news for terrible diseases. Mov Disord Clin Pract 2018;5(4):402–3.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tsai YA, Liu RS, Lirng JF, et al. Treatment of spinocerebellar ataxia with mesenchymal stem cells: a phase I/IIa clinical study. Cell Transplant 2017;26(3):503–12.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2015;14(10):985–91.CrossRefPubMedGoogle Scholar
  21. 21.
    Liu J, Tang TS, Tu H, et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 2009;29(29):9148–62.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kasumu AW, Liang X, Egorova P, Vorontsova D, Bezprozvanny I. 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 2012;32(37):12786–96.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bushart DD, Chopra R, Singh V, Murphy GG, Wulff H, Shakkottai VG. Targeting potassium channels to treat cerebellar ataxia. Ann Clin Transl Neurol 2018;5(3):297–314.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Coarelli G, Brice A, Durr A. Recent advances in understanding dominant spinocerebellar ataxias from clinical and genetic points of view. F1000Research. 2018;7.Google Scholar
  25. 25.
    Antenora A, Bruzzese D, Lieto M, et al. Predictors of survival in spinocerebellar ataxia type 2 population from Southern Italy. Neurol Sci 2018;39(11):1857–60.CrossRefPubMedGoogle Scholar
  26. 26.
    Velazquez-Perez LC, Rodriguez-Labrada R, Fernandez-Ruiz J. Spinocerebellar ataxia type 2: clinicogenetic aspects, mechanistic insights, and management approaches. Front Neurol 2017;8:472.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kim JS, Kwon S, Ki CS, Youn J, Cho JW. The etiologies of chronic progressive cerebellar ataxia in a Korean population. J Clin Neurol 2018;14(3):374–80.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Amarante TRP, Takeda SYM, Teive HAG, Zonta MB. Impact of disease duration on functional status of patients with spinocerebellar ataxia type 2. Arq Neuropsiquiatr 2017;75(11):773–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Diallo A, Jacobi H, Cook A, et al. Survival in patients with spinocerebellar ataxia types 1, 2, 3, and 6 (EUROSCA): a longitudinal cohort study. Lancet Neurol 2018;17(4):327–34.CrossRefPubMedGoogle Scholar
  30. 30.
    Figueroa KP, Coon H, Santos N, Velazquez L, Mederos LA, Pulst SM. Genetic analysis of age at onset variation in spinocerebellar ataxia type 2. Neurol Genet 2017;3(3):e155.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lin YC, Lee YC, Hsu TY, Liao YC, Soong BW. Comparable progression of spinocerebellar ataxias between Caucasians and Chinese. Parkinsonism Relat Disord. 2018.Google Scholar
  32. 32.
    Jacobi H, du Montcel ST, et al. Long-term evolution of patient-reported outcome measures in spinocerebellar ataxias. J Neurol 2018;265(9):2040–51.CrossRefPubMedGoogle Scholar
  33. 33.
    Gispert S, Twells R, Orozco G, et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nat Genet 1993;4(3):295–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Fernandez M, McClain ME, Martinez RA, et al. Late-onset SCA2: 33 CAG repeats are sufficient to cause disease. Neurology. 2000;55(4):569–72.CrossRefPubMedGoogle Scholar
  35. 35.
    Pulst SM. The complex structure of ATXN2 genetic variation. Neurol Genet 2018;4(6):e299.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Almaguer-Mederos LE, Mesa JML, Gonzalez-Zaldivar Y, et al. Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in spinocerebellar ataxia type 2. Clin Genet 2018;94(3–4):346–50.CrossRefPubMedGoogle Scholar
  37. 37.
    Sena LS, Castilhos RM, Mattos EP, et al. Selective forces related to spinocerebellar ataxia type 2. Cerebellum. 2019;18(2):188–94.CrossRefPubMedGoogle Scholar
  38. 38.
    van de Loo S, Eich F, Nonis D, Auburger G, Nowock J. Ataxin-2 associates with rough endoplasmic reticulum. Exp Neurol 2009;215(1):110–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Kiehl TR, Nechiporuk A, Figueroa KP, Keating MT, Huynh DP, Pulst SM. Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochem Biophys Res Commun 2006;339(1):17–24.CrossRefPubMedGoogle Scholar
  40. 40.
    Lastres-Becker I, Brodesser S, Lutjohann D, et al. Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice. Hum Mol Genet 2008;17(10):1465–81.CrossRefPubMedGoogle Scholar
  41. 41.
    Pfeffer M, Gispert S, Auburger G, Wicht H, Korf HW. Impact of Ataxin-2 knock out on circadian locomotor behavior and PER immunoreaction in the SCN of mice. Chronobiol Int 2017;34(1):129–37.CrossRefPubMedGoogle Scholar
  42. 42.
    Lim C, Allada R. ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila. Science. 2013;340(6134):875–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Zhang Y, Ling J, Yuan C, Dubruille R, Emery P. A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science. 2013;340(6134):879–82.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Seidel K, Siswanto S, Fredrich M, et al. On the distribution of intranuclear and cytoplasmic aggregates in the brainstem of patients with spinocerebellar ataxia type 2 and 3. Brain Pathol 2017;27(3):345–55.CrossRefPubMedGoogle Scholar
  45. 45.
    Lim NS, Kozlov G, Chang TC, 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 2006;281(20):14376–82.CrossRefPubMedGoogle Scholar
  46. 46.
    Lastres-Becker I, Nonis D, Eich F, et al. Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation. Biochim Biophys Acta 2016;1862(9):1558–69.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Nonhoff U, Ralser M, Welzel F, et al. Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol Biol Cell 2007;18(4):1385–96.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Bakthavachalu B, Huelsmeier J, Sudhakaran IP, et al. RNP-granule assembly via Ataxin-2 disordered domains is required for long-term memory and neurodegeneration. Neuron. 2018;98(4):754–66 e4.CrossRefPubMedGoogle Scholar
  49. 49.
    Ostrowski LA, Hall AC, Szafranski KJ, et al. Conserved Pbp1/Ataxin-2 regulates retrotransposon activity and connects polyglutamine expansion-driven protein aggregation to lifespan-controlling rDNA repeats. Commun Biol 2018;1:187.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sen NE, Drost J, Gispert S, et al. Search for SCA2 blood RNA biomarkers highlights Ataxin-2 as strong modifier of the mitochondrial factor PINK1 levels. Neurobiol Dis 2016;96:115–26.CrossRefPubMedGoogle Scholar
  51. 51.
    Li PP, Sun X, Xia G, et al. ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis. Ann Neurol 2016;80(4):600–15.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Fittschen M, Lastres-Becker I, Halbach MV, et al. Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate. Neurogenetics. 2015;16(3):181–92.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Meierhofer D, Halbach M, Sen NE, Gispert S, Auburger G. Ataxin-2 (Atxn2)-knock-out mice show branched chain amino acids and fatty acids pathway alterations. Mol Cell Proteomics 2016;15(5):1728–39.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Halbach MV, Gispert S, Stehning T, Damrath E, Walter M, Auburger G. Atxn2 knockout and CAG42-knock-in cerebellum shows similarly dysregulated expression in calcium homeostasis pathway. Cerebellum. 2017;16(1):68–81.CrossRefPubMedGoogle Scholar
  55. 55.
    Louis ED, Kuo SH, Tate WJ, et al. Heterotopic Purkinje cells: a comparative postmortem study of essential tremor and spinocerebellar ataxias 1, 2, 3, and 6. Cerebellum. 2018;17(2):104–10.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Nibbeling EAR, Duarri A, Verschuuren-Bemelmans CC, et al. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain 2017;140(11):2860–78.CrossRefPubMedGoogle Scholar
  57. 57.
    Aboulhoda BE, Hassan SS. Effect of prenatal tramadol on postnatal cerebellar development: role of oxidative stress. J Chem Neuroanat 2018;94:102–18.CrossRefPubMedGoogle Scholar
  58. 58.
    Squadrone S, Brizio P, Mancini C, Abete MC, Brusco A. Altered homeostasis of trace elements in the blood of SCA2 patients. J Trace Elem Med Biol 2018;47:111–4.CrossRefPubMedGoogle Scholar
  59. 59.
    Guevara-Garcia M, Gil-del Valle L, Velasquez-Perez L, Garcia-Rodriguez JC. Oxidative stress as a cofactor in spinocerebellar ataxia type 2. Redox Rep 2012;17(2):84–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Almaguer-Gotay D, Almaguer-Mederos LE, et al. Spinocerebellar ataxia type 2 is associated with the extracellular loss of superoxide dismutase but not catalase activity. Front Neurol 2017;8:276.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Almaguer-Mederos LE, Almaguer-Gotay D, Aguilera-Rodriguez R, et al. Association of glutathione S-transferase omega polymorphism and spinocerebellar ataxia type 2. J Neurol Sci 2017;372:324–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Monte TL, Pereira FS, Reckziegel EDR, et al. Neurological phenotypes in spinocerebellar ataxia type 2: role of mitochondrial polymorphism A10398G and other risk factors. Parkinsonism Relat Disord 2017;42:54–60.CrossRefPubMedGoogle Scholar
  63. 63.
    Hamzeiy H, Savas D, Tunca C, et al. Elevated global DNA methylation is not exclusive to amyotrophic lateral sclerosis and is also observed in spinocerebellar ataxia types 1 and 2. Neurodegener Dis 2018;18(1):38–48.CrossRefPubMedGoogle Scholar
  64. 64.
    Wilke C, Bender F, Hayer SN, et al. Serum neurofilament light is increased in multiple system atrophy of cerebellar type and in repeat-expansion spinocerebellar ataxias: a pilot study. J Neurol 2018;265(7):1618–24.CrossRefPubMedGoogle Scholar
  65. 65.
    Cuello-Almarales DA, Almaguer-Mederos LE, Vazquez-Mojena Y, et al. Buccal cell micronucleus frequency is significantly elevated in patients with spinocerebellar ataxia type 2. Arch Med Res 2017;48(3):297–302.CrossRefPubMedGoogle Scholar
  66. 66.
    Oz G, Iltis I, Hutter D, Thomas W, Bushara KO, Gomez CM. Distinct neurochemical profiles of spinocerebellar ataxias 1, 2, 6, and cerebellar multiple system atrophy. Cerebellum. 2011;10(2):208–17.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Brouillette AM, Oz G, Gomez CM. Cerebrospinal fluid biomarkers in spinocerebellar ataxia: a pilot study. Dis Markers 2015;2015:413098.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Cagnoli C, Brussino A, Mancini C, et al. Spinocerebellar ataxia tethering PCR: a rapid genetic test for the diagnosis of spinocerebellar ataxia types 1, 2, 3, 6, and 7 by PCR and capillary electrophoresis. J Mol Diagn 2018;20(3):289–97.CrossRefPubMedGoogle Scholar
  69. 69.
    Estrada R, Galarraga J, Orozco G, Nodarse A, Auburger G. Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol 1999;97(3):306–10.CrossRefPubMedGoogle Scholar
  70. 70.
    Martin JJ, Van Regemorter N, Krols L, et al. On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropathol 1994;88(4):277–86.CrossRefPubMedGoogle Scholar
  71. 71.
    Marzi C, Ciulli S, Giannelli M, et al. Structural complexity of the cerebellum and cerebral cortex is reduced in spinocerebellar ataxia type 2. J Neuroimaging 2018;28(6):688–93.CrossRefPubMedGoogle Scholar
  72. 72.
    Han Q, Yang J, Xiong H, Shang H. Voxel-based meta-analysis of gray and white matter volume abnormalities in spinocerebellar ataxia type 2. Brain Behav 2018;8(9):e01099.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Lupo M, Olivito G, Iacobacci C, et al. The cerebellar topography of attention sub-components in spinocerebellar ataxia type 2. Cortex 2018;108:35–49.CrossRefPubMedGoogle Scholar
  74. 74.
    Hernandez-Castillo CR, King M, Diedrichsen J, Fernandez-Ruiz J. Unique degeneration signatures in the cerebellar cortex for spinocerebellar ataxias 2, 3, and 7. Neuroimage Clin 2018;20:931–8.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Baldarcara L, Currie S, Hadjivassiliou M, et al. Consensus paper: radiological biomarkers of cerebellar diseases. Cerebellum. 2015;14(2):175–96.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Mascalchi M, Vella A. Neuroimaging applications in chronic ataxias. Int Rev Neurobiol 2018;143:109–62.CrossRefPubMedGoogle Scholar
  77. 77.
    Reetz K, Rodriguez-Labrada R, Dogan I, et al. Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2. Ann Clin Transl Neurol 2018;5(2):128–37.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Yoshii F, Tomiyasu H, Watanabe R, Ryo M. MRI signal abnormalities of the inferior olivary nuclei in spinocerebellar ataxia type 2. Case Rep Neurol 2017;9(3):267–71.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Mascalchi M, Marzi C, Giannelli M, et al. Histogram analysis of DTI-derived indices reveals pontocerebellar degeneration and its progression in SCA2. PLoS One 2018;13(7):e0200258.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Olivito G, Lupo M, Iacobacci C, et al. Microstructural MRI basis of the cognitive functions in patients with spinocerebellar ataxia type 2. Neuroscience. 2017;366:44–53.CrossRefPubMedGoogle Scholar
  81. 81.
    Adanyeguh IM, Perlbarg V, Henry PG, et al. Autosomal dominant cerebellar ataxias: imaging biomarkers with high effect sizes. Neuroimage Clin 2018;19:858–67.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Ito K, Ohtsuka C, Yoshioka K, et al. Differentiation between multiple system atrophy and other spinocerebellar degenerations using diffusion kurtosis imaging. Acad Radiol. 2019.Google Scholar
  83. 83.
    Velazquez-Perez L, Rodriguez-Labrada R, Torres-Vega R, et al. Central motor conduction time as prodromal biomarker in spinocerebellar ataxia type 2. Mov Disord 2016;31(4):603–4.CrossRefPubMedGoogle Scholar
  84. 84.
    Velazquez-Perez L, Rodriguez-Labrada R, Torres-Vega R, et al. Progression of corticospinal tract dysfunction in pre-ataxic spinocerebellar ataxia type 2: a two-years follow-up TMS study. Clin Neurophysiol 2018;129(5):895–900.CrossRefPubMedGoogle Scholar
  85. 85.
    Velazquez-Perez L, Rodriguez-Labrada R, Torres-Vega R, et al. Abnormal corticospinal tract function and motor cortex excitability in non-ataxic SCA2 mutation carriers: a TMS study. Clin Neurophysiol 2016;127(8):2713–9.CrossRefPubMedGoogle Scholar
  86. 86.
    Velazquez-Perez L, Tunnerhoff J, Rodriguez-Labrada R, et al. Corticomuscular coherence: a novel tool to assess the pyramidal tract dysfunction in spinocerebellar ataxia type 2. Cerebellum. 2017;16(2):602–6.CrossRefPubMedGoogle Scholar
  87. 87.
    Velazquez-Perez L, Tunnerhoff J, Rodriguez-Labrada R, et al. Early corticospinal tract damage in prodromal SCA2 revealed by EEG-EMG and EMG-EMG coherence. Clin Neurophysiol 2017;128(12):2493–502.CrossRefPubMedGoogle Scholar
  88. 88.
    Seshagiri DV, Botta R, Sasidharan A, et al. Assessment of sleep spindle density among genetically positive spinocerebellar ataxias types 1, 2, and 3 patients. Ann Neurosci 2018;25(2):106–11.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Zanatta A, Camargo CHF, Germiniani FMB, Raskin S, de Souza Crippa AC, Teive HAG. Abnormal findings in polysomnographic recordings of patients with spinocerebellar ataxia type 2 (SCA2). Cerebellum. 2019;18(2):196–202.CrossRefPubMedGoogle Scholar
  90. 90.
    Rodriguez-Labrada R, Galicia-Polo L, Canales-Ochoa N, et al. Sleep spindles and K-complex activities are decreased in spinocerebellar ataxia type 2: relationship to memory and motor performances. Sleep Med 2019;60:188–96.CrossRefPubMedGoogle Scholar
  91. 91.
    Abele M, Burk K, Laccone F, Dichgans J, Klockgether T. Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3. J Neurol 2001;248(4):311–4.CrossRefPubMedGoogle Scholar
  92. 92.
    Boesch SM, Frauscher B, Brandauer E, Wenning GK, Hogl B, Poewe W. Disturbance of rapid eye movement sleep in spinocerebellar ataxia type 2. Mov Disord 2006;21(10):1751–4.CrossRefPubMedGoogle Scholar
  93. 93.
    Velazquez-Perez L, Voss U, Rodriguez-Labrada R, et al. Sleep disorders in spinocerebellar ataxia type 2 patients. Neurodegener Dis 2011;8(6):447–54.CrossRefPubMedGoogle Scholar
  94. 94.
    Velazquez-Perez L, Rodriguez-Labrada R, Alvarez-Gonzalez L, et al. Lisuride reduces involuntary periodic leg movements in spinocerebellar ataxia type 2 patients. Cerebellum. 2012;11(4):1051–6.CrossRefPubMedGoogle Scholar
  95. 95.
    Rodriguez-Labrada R, Velazquez-Perez L, Ortega-Sanchez R, et al. Insights into cognitive decline in spinocerebellar Ataxia type 2: a P300 event-related brain potential study. Cerebellum Ataxias 2019;6:3.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Olivito G, Lupo M, Iacobacci C, et al. Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2. J Neurol 2018;265(3):597–606.CrossRefPubMedGoogle Scholar
  97. 97.
    Olivito G, Cercignani M, Lupo M, et al. Neural substrates of motor and cognitive dysfunctions in SCA2 patients: a network based statistics analysis. Neuroimage Clin 2017;14:719–25.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Luo L, Wang J, Lo RY, et al. The initial symptom and motor progression in spinocerebellar ataxias. Cerebellum. 2017;16(3):615–22.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Gan SR, Wang J, Figueroa KP, et al. Postural tremor and ataxia progression in spinocerebellar ataxias. Tremor Other Hyperkinet Mov (N Y). 2017;7:492.Google Scholar
  100. 100.
    Lai RY, Tomishon D, Figueroa KP, et al. Tremor in the degenerative cerebellum: towards the understanding of brain circuitry for tremor. Cerebellum. 2019.Google Scholar
  101. 101.
    Markovic V, Dragasevic-Miskovic NT, Stankovic I, Petrovic I, Svetel M, Kostic VS. Dystonia in patients with spinocerebellar ataxia type 2. Mov Disord Clin Pract 2016;3(3):292–5.CrossRefPubMedGoogle Scholar
  102. 102.
    Schmitz-Hubsch T, Coudert M, Bauer P, et al. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology. 2008;71(13):982–9.CrossRefPubMedGoogle Scholar
  103. 103.
    Kuo PH, Gan SR, Wang J, et al. Dystonia and ataxia progression in spinocerebellar ataxias. Parkinsonism Relat Disord 2017;45:75–80.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Leadbetter R, Weatherall M, Pelosi L. Nerve ultrasound as a diagnostic tool for sensory neuronopathy in spinocerebellar ataxia syndrome. Clin Neurophysiol 2019;130(4):568–72.CrossRefPubMedGoogle Scholar
  105. 105.
    Jensen K, Beylergil SB, Shaikh AG. Slow saccades in cerebellar disease. Cerebellum Ataxias 2019;6:1.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Burk K, Fetter M, Abele M, et al. Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3. J Neurol 1999;246(9):789–97.CrossRefPubMedGoogle Scholar
  107. 107.
    Luis L, Costa J, Munoz E, et al. Vestibulo-ocular reflex dynamics with head-impulses discriminates spinocerebellar ataxias types 1, 2 and 3 and Friedreich ataxia. J Vestib Res 2016;26(3):327–34.CrossRefPubMedGoogle Scholar
  108. 108.
    Seshagiri DV, Pal PK, Jain S, Yadav R. Optokinetic nystagmus in patients with SCA: a bedside test for oculomotor dysfunction grading. Neurology. 2018;91(13):e1255-e61.CrossRefPubMedGoogle Scholar
  109. 109.
    Ronsin S, Hannoun S, Thobois S, et al. A new MRI marker of ataxia with oculomotor apraxia. Eur J Radiol 2019;110:187–92.CrossRefPubMedGoogle Scholar
  110. 110.
    Rosini F, Pretegiani E, Mignarri A, et al. The role of dentate nuclei in human oculomotor control: insights from cerebrotendinous xanthomatosis. J Physiol 2017;595(11):3607–20.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Liang L, Chen T, Wu Y. The electrophysiology of spinocerebellar ataxias. Neurophysiol Clin 2016;46(1):27–34.CrossRefPubMedGoogle Scholar
  112. 112.
    Velazquez-Perez L, Seifried C, Santos-Falcon N, et al. Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia 2. Ann Neurol 2004;56(3):444–7.CrossRefPubMedGoogle Scholar
  113. 113.
    Velazquez-Perez L, Seifried C, Abele M, et al. Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2. Clin Neurophysiol 2009;120(3):632–5.CrossRefPubMedGoogle Scholar
  114. 114.
    Rodriguez-Labrada R, Velazquez-Perez L, Auburger G, et al. Spinocerebellar ataxia type 2: measures of saccade changes improve power for clinical trials. Mov Disord 2016;31(4):570–8.CrossRefPubMedGoogle Scholar
  115. 115.
    Rodriguez-Labrada R, Vazquez-Mojena Y, Canales-Ochoa N, Medrano-Montero J, Velazquez-Perez L. Heritability of saccadic eye movements in spinocerebellar ataxia type 2: insights into an endophenotype marker. Cerebellum Ataxias 2017;4:19.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Kim YE, Jeon B, Farrer MJ, et al. SCA2 family presenting as typical Parkinson’s disease: 34 year follow up. Parkinsonism Relat Disord 2017;40:69–72.CrossRefPubMedGoogle Scholar
  117. 117.
    Woo KA, Lee JY, Jeon B. Familial spinocerebellar ataxia type 2 parkinsonism presenting as intractable oromandibular dystonia. Tremor Other Hyperkinet Mov (N Y). 2019;9:611.Google Scholar
  118. 118.
    Nkiliza A, Mutez E, Simonin C, et al. RNA-binding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease. Neurobiol Dis 2016;96:312–22.CrossRefPubMedGoogle Scholar
  119. 119.
    Kim YE, Oh KW, Noh MY, et al. Analysis of ATXN2 trinucleotide repeats in Korean patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2018;67:201 e5–e8.CrossRefGoogle Scholar
  120. 120.
    de Silva R, Greenfield J, Cook A, et al. Guidelines on the diagnosis and management of the progressive ataxias. Orphanet J Rare Dis 2019;14(1):51.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Rodriguez-Diaz JC, Velazquez-Perez L, Rodriguez Labrada R, et al. Neurorehabilitation therapy in spinocerebellar ataxia type 2: a 24-week, rater-blinded, randomized, controlled trial. Mov Disord 2018;33(9):1481–7.CrossRefPubMedGoogle Scholar
  122. 122.
    Zesiewicz TA, Wilmot G, Kuo SH, et al. Comprehensive systematic review summary: treatment of cerebellar motor dysfunction and ataxia: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(10):464–71.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Anderson CJ, Figueroa KP, Dorval AD, Pulst SM. Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat. Ann Neurol. 2019.Google Scholar
  124. 124.
    Huynh DP, Figueroa K, Hoang N, Pulst SM. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet 2000;26(1):44–50.CrossRefPubMedGoogle Scholar
  125. 125.
    Kasumu AW, Hougaard C, Rode F, et al. Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. Chem Biol 2012;19(10):1340–53.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Egorova PA, Zakharova OA, Vlasova OL, Bezprozvanny IB. In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model. J Neurophysiol 2016;115(6):2840–51.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Egorova PA, Gavrilova AV, Bezprozvanny IB. In vivo analysis of the climbing fiber-Purkinje cell circuit in SCA2-58Q transgenic mouse model. Cerebellum. 2018;17(5):590–600.CrossRefPubMedGoogle Scholar
  128. 128.
    Aguiar J, Fernandez J, Aguilar A, et al. Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specific Purkinje cell degeneration in transgenic mice. Neurosci Lett 2006;392(3):202–6.CrossRefPubMedGoogle Scholar
  129. 129.
    Damrath E, Heck MV, Gispert S, et al. ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice. PLoS Genet 2012;8(8):e1002920.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Hansen ST, Meera P, Otis TS, Pulst SM. Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet 2013;22(2):271–83.CrossRefPubMedGoogle Scholar
  131. 131.
    Pflieger LT, Dansithong W, Paul S, et al. Gene co-expression network analysis for identifying modules and functionally enriched pathways in SCA2. Hum Mol Genet 2017;26(16):3069–80.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Dansithong W, Paul S, Figueroa KP, et al. Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model. PLoS Genet 2015;11(4):e1005182.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Chuang CY, Yang CC, Soong BW, et al. Modeling spinocerebellar ataxias 2 and 3 with iPSCs reveals a role for glutamate in disease pathology. Sci Rep 2019;9(1):1166.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Marthaler AG, Schmid B, Tubsuwan A, et al. Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H196. Stem Cell Res 2016;16(1):199–201.CrossRefPubMedGoogle Scholar
  135. 135.
    Maguire JA, Gagne AL, Gonzalez-Alegre P, 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 2019;34:101361.CrossRefPubMedGoogle Scholar
  136. 136.
    Todd TW, Lim J. Aggregation formation in the polyglutamine diseases: protection at a cost? Mol Cells 2013;36(3):185–94.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Koyano S, Yagishita S, Kuroiwa Y, Tanaka F, Uchihara T. 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 2014;24(6):599–606.CrossRefPubMedGoogle Scholar
  138. 138.
    Ueda M, Li S, Itoh M, et al. Polyglutamine expansion disturbs the endoplasmic reticulum formation, leading to caspase-7 activation through Bax. Biochem Biophys Res Commun 2014;443(4):1232–8.CrossRefPubMedGoogle Scholar
  139. 139.
    Cornelius N, Wardman JH, Hargreaves IP, et al. Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fibroblasts: effect of coenzyme Q10 supplementation on these parameters. Mitochondrion. 2017;34:103–14.CrossRefPubMedGoogle Scholar
  140. 140.
    Lo RY, Figueroa KP, Pulst SM, et al. Coenzyme Q10 and spinocerebellar ataxias. Mov Disord 2015;30(2):214–20.CrossRefPubMedGoogle Scholar
  141. 141.
    Brown AS, Meera P, Altindag B, et al. MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias. Proc Natl Acad Sci U S A 2018;115(52):E12407-E16.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Verbeek DS, Goedhart J, Bruinsma L, Sinke RJ, Reits EA. PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling. J Cell Sci 2008;121(Pt 14):2339–49.CrossRefPubMedGoogle Scholar
  143. 143.
    Shimobayashi E, Kapfhammer JP. Calcium signaling, PKC gamma, IP3R1 and CAR8 link spinocerebellar ataxias and Purkinje cell dendritic development. Curr Neuropharmacol 2018;16(2):151–9.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Chopra R, Wasserman AH, Pulst SM, De Zeeuw CI, Shakkottai VG. Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia. Hum Mol Genet 2018;27(8):1396–410.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D. NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 2003;6(10):1072–8.CrossRefPubMedGoogle Scholar
  146. 146.
    Ferro A, Qu W, Lukowicz A, Svedberg D, Johnson A, Cvetanovic M. 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 2018;13(7):e0200013.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Li YX, Sibon OCM, Dijkers PF. Inhibition of NF-kappaB in astrocytes is sufficient to delay neurodegeneration induced by proteotoxicity in neurons. J Neuroinflammation 2018;15(1):261.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Schwaller B, Meyer M, Schiffmann S. ‘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. 2002;1(4):241–58.CrossRefPubMedGoogle Scholar
  149. 149.
    Kreiner L, Christel CJ, Benveniste M, Schwaller B, Lee A. Compensatory regulation of Cav2.1 Ca2+ channels in cerebellar Purkinje neurons lacking parvalbumin and calbindin D-28k. J Neurophysiol 2010;103(1):371–81.CrossRefPubMedGoogle Scholar
  150. 150.
    Kano M, Nakayama H, Hashimoto K, Kitamura K, Sakimura K, Watanabe M. Calcium-dependent regulation of climbing fibre synapse elimination during postnatal cerebellar development. J Physiol 2013;591(Pt 13):3151–8.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Barnes JA, Ebner BA, Duvick LA, et al. Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice. J Neurosci 2011;31(36):12778–89.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Long C, Grueter CE, Song K, et al. Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor. Proc Natl Acad Sci U S A 2014;111(31):11521–6.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Kawaguchi SY, Hirano T. Gating of long-term depression by Ca2+/calmodulin-dependent protein kinase II through enhanced cGMP signalling in cerebellar Purkinje cells. J Physiol 2013;591(Pt 7):1707–30.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Fukumitsu K, Hatsukano T, Yoshimura A, Heuser J, Fujishima K, Kengaku M. Mitochondrial fission protein Drp1 regulates mitochondrial transport and dendritic arborization in cerebellar Purkinje cells. Mol Cell Neurosci 2016;71:56–65.CrossRefPubMedGoogle Scholar
  155. 155.
    Di Bella D, Lazzaro F, Brusco A, et al. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet 2010;42(4):313–21.CrossRefPubMedGoogle Scholar
  156. 156.
    Alberts B. Molecular biology of the cell. 4th ed. New York: Garland Science; 2002. xxxiv, 1548 p. p.Google Scholar
  157. 157.
    Keebler MV, Taylor CW. Endogenous signalling pathways and caged IP3 evoke Ca(2+) puffs at the same abundant immobile intracellular sites. J Cell Sci 2017;130(21):3728–39.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Hirai H, Kano M. Type 1 metabotropic glutamate receptor and its signaling molecules as therapeutic targets for the treatment of cerebellar disorders. Curr Opin Pharmacol 2018;38:51–8.CrossRefPubMedGoogle Scholar
  159. 159.
    Serra HG, Duvick L, Zu T, et al. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006;127(4):697–708.CrossRefPubMedGoogle Scholar
  160. 160.
    Gold DA, Baek SH, Schork NJ, et al. RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways. Neuron. 2003;40(6):1119–31.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Orr HT. SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis. Prog Neurobiol 2012;99(3):179–85.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Meera P, Pulst S, Otis T. A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2. eLife. 2017;6.Google Scholar
  163. 163.
    Collins AJ, Foley RN, Herzog C, et al. US Renal Data System 2012 annual data report. Am J Kidney Dis 2013;61(1 Suppl 1):A7, e1-476.CrossRefPubMedGoogle Scholar
  164. 164.
    Meera P, Pulst SM, Otis TS. Cellular and circuit mechanisms underlying spinocerebellar ataxias. J Physiol 2016;594(16):4653–60.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Puorro G, Marsili A, Sapone F, et al. Peripheral markers of autophagy in polyglutamine diseases. Neurol Sci 2018;39(1):149–52.CrossRefPubMedGoogle Scholar
  166. 166.
    Paul S, Dansithong W, Figueroa KP, Scoles DR, Pulst SM. Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration. Nat Commun 2018;9(1):3648.CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Ferro A, Sheeler C, Rosa JG, Cvetanovic M. Role of microglia in ataxias. J Mol Biol. 2019.Google Scholar
  168. 168.
    Thion MS, Low D, Silvin A, et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell. 2018;172(3):500–16 e16.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Nakayama H, Abe M, Morimoto C, et al. Microglia permit climbing fiber elimination by promoting GABAergic inhibition in the developing cerebellum. Nat Commun 2018;9(1):2830.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Ebner BA, Ingram MA, Barnes JA, et al. Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum. J Neurosci 2013;33(13):5806–20.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Cvetanovic M, Ingram M, Orr H, Opal P. Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1. Neuroscience. 2015;289:289–99.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Qu W, Johnson A, Kim JH, Lukowicz A, Svedberg D, Cvetanovic M. Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice. J Neuroinflammation 2017;14(1):107.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Llinas R, Sugimori M. Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices. J Physiol 1980;305:197–213.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Llinas R, Sugimori M. Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J Physiol 1980;305:171–95.CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Raman IM, Bean BP. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J Neurosci 1997;17(12):4517–26.CrossRefPubMedGoogle Scholar
  176. 176.
    Raman IM, Bean BP. Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J Neurosci 1999;19(5):1663–74.CrossRefPubMedGoogle Scholar
  177. 177.
    Nam SC, Hockberger PE. Analysis of spontaneous electrical activity in cerebellar Purkinje cells acutely isolated from postnatal rats. J Neurobiol 1997;33(1):18–32.CrossRefPubMedGoogle Scholar
  178. 178.
    Womack M, Khodakhah K. Active contribution of dendrites to the tonic and trimodal patterns of activity in cerebellar Purkinje neurons. J Neurosci 2002;22(24):10603–12.CrossRefPubMedGoogle Scholar
  179. 179.
    Smith SL, Otis TS. Persistent changes in spontaneous firing of Purkinje neurons triggered by the nitric oxide signaling cascade. J Neurosci 2003;23(2):367–72.CrossRefPubMedGoogle Scholar
  180. 180.
    De Zeeuw CI, Hoebeek FE, Bosman LW, Schonewille M, Witter L, Koekkoek SK. Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci 2011;12(6):327–44.CrossRefPubMedGoogle Scholar
  181. 181.
    Hoebeek FE, Stahl JS, van Alphen AM, et al. Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control. Neuron. 2005;45(6):953–65.CrossRefPubMedGoogle Scholar
  182. 182.
    Alvina K, Khodakhah K. The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia. J Neurosci 2010;30(21):7258–68.CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Dell’Orco JM, Wasserman AH, Chopra R, et al. Neuronal atrophy early in degenerative ataxia is a compensatory mechanism to regulate membrane excitability. J Neurosci 2015;35(32):11292–307.CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Mark MD, Krause M, Boele HJ, et al. Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity. J Neurosci 2015;35(23):8882–95.CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Shakkottai VG, do Carmo Costa M, Dell’Orco JM, Sankaranarayanan A, Wulff H, Paulson HL. Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3. J Neurosci 2011;31(36):13002–14.CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Walter JT, Alvina K, Womack MD, Chevez C, Khodakhah K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci 2006;9(3):389–97.CrossRefPubMedGoogle Scholar
  187. 187.
    Chopra R, Shakkottai VG. Translating cerebellar Purkinje neuron physiology to progress in dominantly inherited ataxia. Future Neurol 2014;9(2):187–96.CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Dell’Orco JM, Pulst SM, Shakkottai VG. Potassium channel dysfunction underlies Purkinje neuron spiking abnormalities in spinocerebellar ataxia type 2. Hum Mol Genet 2017;26(20):3935–45.CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Bushart DD, Shakkottai VG. Ion channel dysfunction in cerebellar ataxia. Neurosci Lett 2019;688:41–8.CrossRefPubMedGoogle Scholar
  190. 190.
    Coutelier M, Coarelli G, Monin ML, et al. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies. Brain 2017;140(6):1579–94.CrossRefPubMedGoogle Scholar
  191. 191.
    Jones JM, Dionne L, Dell’Orco J, 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 2016;89:36–45.CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Lee KH, Mathews PJ, Reeves AM, et al. Circuit mechanisms underlying motor memory formation in the cerebellum. Neuron. 2015;86(2):529–40.CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Lang EJ, Apps R, Bengtsson F, et al. The roles of the olivocerebellar pathway in motor learning and motor control. A consensus paper. Cerebellum. 2017;16(1):230–52.CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Kuo SH, Lin CY, Wang J, et al. Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases. Acta Neuropathol 2017;133(1):121–38.CrossRefPubMedGoogle Scholar
  195. 195.
    Burroughs A, Wise AK, Xiao J, et al. The dynamic relationship between cerebellar Purkinje cell simple spikes and the spikelet number of complex spikes. J Physiol 2017;595(1):283–99.CrossRefPubMedGoogle Scholar
  196. 196.
    Davie JT, Clark BA, Hausser M. The origin of the complex spike in cerebellar Purkinje cells. J Neurosci 2008;28(30):7599–609.CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    van Roon-Mom WMC, Roos RAC, de Bot ST. Dose-dependent lowering of mutant Huntingtin using antisense oligonucleotides in Huntington disease patients. Nucleic Acid Ther 2018;28(2):59–62.CrossRefPubMedGoogle Scholar
  198. 198.
    Becker LA, Huang B, Bieri G, et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017;544(7650):367–71.CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Ashizawa AT, Holt J, Faust K, et al. Intravenously administered novel liposomes, DCL64, deliver oligonucleotides to cerebellar purkinje cells. Cerebellum. 2019;18(1):99–108.CrossRefPubMedGoogle Scholar
  200. 200.
    Chang YK, Chen MH, Chiang YH, et al. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci 2011;18:54.CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Vogel MW, Caston J, Yuzaki M, Mariani J. The Lurcher mouse: fresh insights from an old mutant. Brain Res 2007;1140:4–18.CrossRefPubMedGoogle Scholar
  202. 202.
    Jones J, Jaramillo-Merchan J, Bueno C, Pastor D, Viso-Leon M, Martinez S. Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia. Neurobiol Dis 2010;40(2):415–23.CrossRefPubMedGoogle Scholar
  203. 203.
    Bushart DD, Murphy GG, Shakkottai VG. Precision medicine in spinocerebellar ataxias: treatment based on common mechanisms of disease. Ann Transl Med 2016;4(2):25.PubMedPubMedCentralGoogle Scholar
  204. 204.
    Womack MD, Khodakhah K. Somatic and dendritic small-conductance calcium-activated potassium channels regulate the output of cerebellar Purkinje neurons. J Neurosci 2003;23(7):2600–7.CrossRefPubMedGoogle Scholar
  205. 205.
    Alvina K, Khodakhah K. KCa channels as therapeutic targets in episodic ataxia type-2. J Neurosci 2010;30(21):7249–57.CrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Cho LT, Alexandrou AJ, Torella R, et al. An intracellular allosteric modulator binding pocket in SK2 ion channels is shared by multiple chemotypes. Structure. 2018;26(4):533–44 e3.CrossRefPubMedGoogle Scholar
  207. 207.
    Nagai Y, Tucker T, Ren H, et al. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem 2000;275(14):10437–42.CrossRefPubMedGoogle Scholar
  208. 208.
    Nagai Y, Fujikake N, Ohno K, et al. Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet 2003;12(11):1253–9.CrossRefPubMedGoogle Scholar
  209. 209.
    Popiel HA, Nagai Y, Fujikake N, Toda T. Delivery of the aggregate inhibitor peptide QBP1 into the mouse brain using PTDs and its therapeutic effect on polyglutamine disease mice. Neurosci Lett 2009;449(2):87–92.CrossRefPubMedGoogle Scholar
  210. 210.
    Lecerf JM, Shirley TL, Zhu Q, et al. Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington’s disease. Proc Natl Acad Sci U S A 2001;98(8):4764–9.CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Wolfgang WJ, Miller TW, Webster JM, et al. Suppression of Huntington’s disease pathology in Drosophila by human single-chain Fv antibodies. Proc Natl Acad Sci U S A 2005;102(32):11563–8.CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Wang CE, Zhou H, McGuire JR, et al. Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol 2008;181(5):803–16.CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Chen X, Wu J, Luo Y, et al. Expanded polyglutamine-binding peptoid as a novel therapeutic agent for treatment of Huntington’s disease. Chem Biol 2011;18(9):1113–25.CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Reis SD, Pinho BR, Oliveira JMA. Modulation of molecular chaperones in Huntington’s disease and other polyglutamine disorders. Mol Neurobiol 2017;54(8):5829–54.CrossRefPubMedGoogle Scholar
  215. 215.
    Kampinga HH, Bergink S. Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurol 2016;15(7):748–59.CrossRefPubMedGoogle Scholar
  216. 216.
    Al-Ramahi I, Lam YC, Chen HK, et al. CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem 2006;281(36):26714–24.CrossRefPubMedGoogle Scholar
  217. 217.
    Williams AJ, Knutson TM, Colomer Gould VF, Paulson HL. In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis. Neurobiol Dis 2009;33(3):342–53.CrossRefPubMedGoogle Scholar
  218. 218.
    Cummings CJ, Sun Y, Opal P, et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 2001;10(14):1511–8.CrossRefPubMedGoogle Scholar
  219. 219.
    Fujimoto M, Takaki E, Hayashi T, et al. Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J Biol Chem 2005;280(41):34908–16.CrossRefPubMedGoogle Scholar
  220. 220.
    Helmlinger D, Bonnet J, Mandel JL, Trottier Y, Devys D. Hsp70 and Hsp40 chaperones do not modulate retinal phenotype in SCA7 mice. J Biol Chem 2004;279(53):55969–77.CrossRefPubMedGoogle Scholar
  221. 221.
    Neef DW, Turski ML, Thiele DJ. Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol 2010;8(1):e1000291.CrossRefPubMedPubMedCentralGoogle Scholar
  222. 222.
    Nelson VK, Ali A, Dutta N, et al. Azadiradione ameliorates polyglutamine expansion disease in Drosophila by potentiating DNA binding activity of heat shock factor 1. Oncotarget. 2016;7(48):78281–96.CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    van Waarde-Verhagen M, Kampinga HH. Measurement of chaperone-mediated effects on polyglutamine protein aggregation by the filter trap assay. Methods Mol Biol 2018;1709:59–74.CrossRefPubMedGoogle Scholar
  224. 224.
    Pulsinelli WA. Selective neuronal vulnerability: morphological and molecular characteristics. Prog Brain Res 1985;63:29–37.CrossRefPubMedGoogle Scholar
  225. 225.
    Jaspers NG, Gatti RA, Baan C, Linssen PC, Bootsma D. Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet 1988;49(4):259–63.CrossRefPubMedGoogle Scholar
  226. 226.
    Jung J, Bonini N. CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science. 2007;315(5820):1857–9.CrossRefPubMedGoogle Scholar
  227. 227.
    Sinha S, Goyal S, Somvanshi P, Grover A. Mechanistic insights into the binding of class IIa HDAC inhibitors toward spinocerebellar ataxia type-2: a 3D-QSAR and pharmacophore modeling approach. Front Neurosci 2016;10:606.PubMedGoogle Scholar
  228. 228.
    Hubert L, Jr., Lin Y, Dion V, Wilson JH. Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Hum Mol Genet 2011;20(24):4822–30.CrossRefPubMedPubMedCentralGoogle Scholar
  229. 229.
    Gao R, Liu Y, Silva-Fernandes A, et al. Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3. PLoS Genet 2015;11(1):e1004834.CrossRefPubMedPubMedCentralGoogle Scholar
  230. 230.
    Wan L, Xu K, Chen Z, Tang B, Jiang H. Roles of post-translational modifications in spinocerebellar ataxias. Front Cell Neurosci 2018;12:290.CrossRefPubMedPubMedCentralGoogle Scholar
  231. 231.
    Asada A, Yamazaki R, Kino Y, et al. Cyclin-dependent kinase 5 phosphorylates and induces the degradation of ataxin-2. Neurosci Lett 2014;563:112–7.CrossRefPubMedGoogle Scholar
  232. 232.
    Tsoi H, Lau TC, Tsang SY, Lau KF, Chan HY. CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci U S A 2012;109(33):13428–33.CrossRefPubMedPubMedCentralGoogle Scholar
  233. 233.
    Zhang Q, Chen ZS, An Y, et al. A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases. RNA. 2018;24(4):486–98.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Laboratory of Molecular NeurodegenerationPeter the Great St.Petersburg Polytechnic UniversitySt. PetersburgRussia
  2. 2.Department of PhysiologyUniversity of Texas Southwestern Medical CenterDallasUSA

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