Skip to main content

Advertisement

SpringerLink
Log in

Electrophysiological Studies Support Utility of Positive Modulators of SK Channels for the Treatment of Spinocerebellar Ataxia Type 2

  • Review
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

Spinocerebellar ataxia type 2 (SCA2) is an incurable hereditary disorder accompanied by cerebellar degeneration following ataxic symptoms. The causative gene for SCA2 is ATXN2. The ataxin-2 protein is involved in RNA metabolism; the polyQ expansion may interrupt ataxin-2 interaction with its molecular targets, thus representing a loss-of-function mutation. However, mutant ataxin-2 protein also displays the features of gain-of-function mutation since it forms the aggregates in SCA2 cells and also enhances the IP3-induced calcium release in affected neurons. The cerebellar Purkinje cells (PCs) are primarily affected in SCA2. Their tonic pacemaker activity is crucial for the proper cerebellar functioning. Disturbances in PC pacemaking are observed in many ataxic disorders. The abnormal intrinsic pacemaking was reported in mouse models of episodic ataxia type 2 (EA2), SCA1, SCA2, SCA3, SCA6, Huntington’s disease (HD), and in some other murine models of the disorders associated with the cerebellar degeneration. In our studies using SCA2-58Q transgenic mice via cerebellar slice recording and in vivo recording from urethane-anesthetized mice and awake head-fixed mice, we have demonstrated the impaired firing frequency and irregularity of PCs in these mice. PC pacemaker activity is regulated by SK channels. The pharmacological activation of SK channels has demonstrated some promising results in the electrophysiological experiments on EA2, SCA1, SCA2, SCA3, SCA6, HD mice, and also on mutant CACNA1A mice. In our studies, we have reported that the SK activators CyPPA and NS309 converted bursting activity into tonic, while oral treatment with CyPPA and NS13001 significantly improved motor performance and PC morphology in SCA2 mice. The i.p. injections of chlorzoxazone (CHZ) during in vivo recording sessions converted bursting cells into tonic in anesthetized SCA2 mice. And, finally, long-term injections of CHZ recovered the precision of PC pacemaking activity in awake SCA2 mice and alleviated their motor decline. Thus, the SK activation can be used as a potential way to treat SCA2 and other diseases accompanied by cerebellar degeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ashizawa T, Oz G, Paulson HL. Spinocerebellar ataxias: prospects and challenges for therapy development. Nat Rev Neurol. 2018;14(10):590–605.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  3. Paulson HL, et al. Polyglutamine spinocerebellar ataxias - from genes to potential treatments. Nat Rev Neurosci. 2017;18(10):613–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Scoles DR, Pulst SM. Spinocerebellar ataxia type 2. Adv Exp Med Biol. 2018;1049:175–95.

    Article  CAS  PubMed  Google Scholar 

  5. Buijsen RAM, et al. Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias. Neurotherapeutics. 2019;16(2):263–286.

  6. Egorova PA, Bezprozvanny IB. Molecular mechanisms and therapeutics for spinocerebellar ataxia type 2. Neurotherapeutics. 2019;16(4):1050–73.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Burk K, et al. Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J Neurol. 2003;250(2):207–11.

    Article  CAS  PubMed  Google Scholar 

  8. Fancellu R, et al. Longitudinal study of cognitive and psychiatric functions in spinocerebellar ataxia types 1 and 2. J Neurol. 2013;260(12):3134–43.

    Article  PubMed  Google Scholar 

  9. Gigante AF, et al. The relationships between ataxia and cognition in spinocerebellar ataxia type 2. Cerebellum. 2020;19(1):40–7.

    Article  CAS  PubMed  Google Scholar 

  10. Moriarty A, et al. A longitudinal investigation into cognition and disease progression in spinocerebellar ataxia types 1, 2, 3, 6, and 7. Orphanet J Rare Dis. 2016;11(1):82.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Paneque HM, et al. Type 2 spinocerebellar ataxia: an experience in psychological rehabilitation. Rev Neurol. 2001;33(11):1001–5.

    CAS  PubMed  Google Scholar 

  12. Liu J, et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci. 2009;29(29):9148–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kasumu AW, 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. 2012;32(37):12786–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chuang CY, et al. Modeling spinocerebellar ataxias 2 and 3 with iPSCs reveals a role for glutamate in disease pathology. Sci Rep. 2019;9(1):1166.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Walter JT, et al. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci. 2006;9(3):389–97.

    Article  CAS  PubMed  Google Scholar 

  16. Shakkottai VG, et al. Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3. J Neurosci. 2011;31(36):13002–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gao Z, et al. Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice. J Neurosci. 2012;32(44):15533–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hansen ST, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  19. Dell’Orco JM, et al. Neuronal atrophy early in degenerative ataxia is a compensatory mechanism to regulate membrane excitability. J Neurosci. 2015;35(32):11292–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mark MD, et al. Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity. J Neurosci. 2015;35(23):8882–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kasumu AW, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Egorova PA, et al. In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model. J Neurophysiol. 2016;115(6):2840–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Egorova PA, Gavrilova AV, Bezprozvanny IB. In vivo analysis of the spontaneous firing of cerebellar Purkinje cells in awake transgenic mice that model spinocerebellar ataxia type 2. Cell Calcium. 2021;93:102319.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meera P, Pulst SM, Otis TS. Cellular and circuit mechanisms underlying spinocerebellar ataxias. J Physiol. 2016;594(16):4653–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bushart DD, et al. Targeting potassium channels to treat cerebellar ataxia. Ann Clin Transl Neurol. 2018;5(3):297–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alvina K, Khodakhah K. The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia. J Neurosci. 2010;30(21):7258–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Alvina K, Khodakhah K. KCa channels as therapeutic targets in episodic ataxia type-2. J Neurosci. 2010;30(21):7249–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Romano S, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14(10):985–91.

    Article  CAS  PubMed  Google Scholar 

  30. Gispert S, 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.

    Article  CAS  PubMed  Google Scholar 

  31. Fernandez M, et al. Late-onset SCA2: 33 CAG repeats are sufficient to cause disease. Neurology. 2000;55(4):569–72.

    Article  CAS  PubMed  Google Scholar 

  32. Seidel K, 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.

    Article  CAS  PubMed  Google Scholar 

  33. Mark MD, et al. Keeping our calcium in balance to maintain our balance. Biochem Biophys Res Commun. 2017;483(4):1040–50.

    Article  CAS  PubMed  Google Scholar 

  34. Egorova PA, Bezprozvanny IB. Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders. FEBS J. 2018;285(19):3547–65.

    Article  CAS  PubMed  Google Scholar 

  35. Hisatsune C, Hamada K, Mikoshiba K. Ca2+ signaling and spinocerebellar ataxia. Biochim Biophys Acta Mol Cell Res. 2018;1865(11 Pt B):1733–1744.

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hoebeek FE, et al. Increased noise level of Purkinje cell activities minimizes impact of their modulation during sensorimotor control. Neuron. 2005;45(6):953–65.

    Article  CAS  PubMed  Google Scholar 

  38. Dougherty SE, et al. Disruption of Purkinje cell function prior to huntingtin accumulation and cell loss in an animal model of Huntington disease. Exp Neurol. 2012;236(1):171–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dougherty SE, et al. Purkinje cell dysfunction and loss in a knock-in mouse model of Huntington disease. Exp Neurol. 2013;240:96–102.

    Article  CAS  PubMed  Google Scholar 

  40. Egorova PA, Gavrilova AV, Bezprozvanny IB. Ataxic symptoms in Huntington’s disease transgenic mouse model are alleviated by chlorzoxazone. Front Neurosci. 2020;14:279.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Isaksen TJ, et al. Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump. PLoS Genet. 2017;13(5):e1006763.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Stay TL, et al. In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy. Dis Model Mech. 2019;13(2):dmm040840.

  43. Bushart DD, et al. A chlorzoxazone-baclofen combination improves cerebellar impairment in spinocerebellar ataxia type 1. Mov Disord. 2021;36(3):622–31.

    Article  CAS  PubMed  Google Scholar 

  44. 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):3935–3945.

  45. Jayabal S, et al. 4-Aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6. Sci Rep. 2016;6:29489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kislin M, et al. Flat-floored air-lifted platform: a new method for combining behavior with microscopy or electrophysiology on awake freely moving rodents. J Vis Exp. 2014; (88): e51869

  48. Scoles DR, et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature. 2017;544(7650):362–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chang YK, et al. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci. 2011;18:54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tsai YA, et al. Treatment of spinocerebellar ataxia with mesenchymal stem cells: a phase I/IIa clinical study. Cell Transplant. 2017;26(3):503–12.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cummings CJ, 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.

    Article  CAS  PubMed  Google Scholar 

  52. Fujimoto M, et al. Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J Biol Chem. 2005;280(41):34908–16.

    Article  CAS  PubMed  Google Scholar 

  53. Helmlinger D, et al. Hsp70 and Hsp40 chaperones do not modulate retinal phenotype in SCA7 mice. J Biol Chem. 2004;279(53):55969–77.

    Article  CAS  PubMed  Google Scholar 

  54. Grasselli G, et al. SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning-specific memory traces. PLoS Biol. 2020;18(1):e3000596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

IB is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer’s Disease Research.

Funding

This research was done by Peter the Great St. Petersburg Polytechnic University and supported under the strategic academic leadership program “Priority 2030” of the Russian Federation (Agreement 75–15-2021–1333 30.09.2021 to SPbPU) and by the National Institutes of Health grant R01NS056224 (IB).

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia

    Polina A. Egorova & Ilya B. Bezprozvanny

  2. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Ilya B. Bezprozvanny

Authors
  1. Polina A. Egorova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilya B. Bezprozvanny
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Polina A. Egorova or Ilya B. Bezprozvanny.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Egorova, P.A., Bezprozvanny, I.B. Electrophysiological Studies Support Utility of Positive Modulators of SK Channels for the Treatment of Spinocerebellar Ataxia Type 2. Cerebellum 21, 742–749 (2022). https://doi.org/10.1007/s12311-021-01349-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-021-01349-1

Keywords

Search

Navigation