Experience of mGLuR1 Gene Therapy in Transgenic Models of SCA1 Mice

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previously, we examined a mouse model of SCA1 and found a progressive functional impairment of metabotropic glutamate receptor (mGluR) signaling including dendritic Ca²⁺ signals and a consequent loss of short- and long-term synaptic plasticity at parallel fiber-Purkinje cell synapses in the early disease stage (12 postnatal weeks) prior to Purkinje cell death. According to this findings we suspected that enhancement of mGluR signaling by virus expression of mGluR1 selectively in Purkinje cells should lead to an improvement of motor performance in SCA1 mice. For this aim we construct viruses in a head of adeno-associated virus and murine stem cell virus promoters expressing mGluR1 and green fluorescent protein. Unfortunately, overexpression of this gene constructs gives the opposite effect. Examination of this phenomena leads to understanding of mGluR1 dependent mechanisms of dendritic arborization, synaptogenesis and synaptic plasticity in Purkinje cells. Thus, we found that mGluR1 signaling is a critical but not unique molecular in SCA1 pathogenesis. Also this negative result shows the complicity and ambiguousness of virus therapy benefit.

1. Orr H.T. SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis. Prog Neurobiol 2012; 99(3): 179–185, https://doi.org/10.1016/j.pneurobio.2012.04.003.
2. Serra H.G., Duvick L., Zu T., Carlson K., Stevens S., Jorgensen N., Lysholm A., Burright E., Zoghbi H.Y., Clark H.B., Andresen J.M., Orr H.T. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 2006; 127(4): 697–708, https://doi.org/10.1016/j.cell.2006.09.036.
3. Sidman R.L., Lane P.W., Dickie M.M. Staggerer, a new mutation in the mouse affecting the cerebellum. Science 1962; 137(3530): 610–612, https://doi.org/10.1126/science.137.3530.610.
4. Mitsumura K., Hosoi N., Furuya N., Hirai H. Disruption of metabotropic glutamate receptor signalling is a major defect at cerebellar parallel fibre-Purkinje cell synapses in staggerer mutant mice. J Physiol 2011; 589(Pt 13): 3191–3209, https://doi.org/10.1113/jphysiol.2011.207563.
5. Konno A., Shuvaev A.N., Miyake N., Miyake K., Iizuka A., Matsuura S., Huda F., Nakamura K., Yanagi S., Shimada T., Hirai H. Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells. Cerebellum 2014; 13(1): 29–41, https://doi.org/10.1007/s12311-013-0516-5.
6. Ferraguti F., Crepaldi L., Nicoletti F. Metabotropic glutamate 1 receptor: current concepts and perspectives. Pharmacol Rev 2008; 60(4): 536–581, https://doi.org/10.1124/pr.108.000166.
7. Kano M., Hashimoto K., Tabata T. Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination. Philos Trans R Soc Lond B Biol Sci 2008; 363(1500): 2173–2186, https://doi.org/10.1098/rstb.2008.2270.
8. Hartmann J., Dragicevic E., Adelsberger H., Henning A., Sumser M., Abramowitz J., Blum R., Dietrich A., Freichel M., Flockerzi V., Birnbaumer L., Konnerth A. TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 2008; 59(3): 392–398, https://doi.org/10.1016/j.neuron.2008.06.009.
9. Burright E.N., Clark H.B., Servadio A., Matilla T., Feddersen R.M., Yunis W.S., Duvick L.A., Zoghbi H.Y., Orr H.T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 1995; 82(6): 937–948, https://doi.org/10.1016/0092-86 74(95)90273-2.
10. Torashima T., Okoyama S., Nishizaki T., Hirai H. In vivo transduction of murine cerebellar Purkinje cells by HIV-derived lentiviral vectors. Brain Res 2006; 1082(1): 11–22, https://doi.org/10.1016/j.brainres.2006.01.104.
11. Niwa H., Yamamura K., Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 1991; 108(2): 193–199, https://doi.org/10.1016/0378-1119(91)90434-d.
12. Takayama K., Torashima T., Horiuchi H., Hirai H. Purkinje-cell-preferential transduction by lentiviral vectors with the murine stem cell virus promoter. Neurosci Lett 2008; 443(1): 7–11, https://doi.org/10.1016/j.neulet.2008.07.058.
13. Oue M., Mitsumura K., Torashima T., Koyama C., Yamaguchi H., Furuya N., Hirai H. Characterization of mutant mice that express polyglutamine in cerebellar Purkinje cells. Brain Res 2009; 1255: 9–17, https://doi.org/10.1016/j.brainres.2008.12.014.
14. Tamayose K., Hirai Y., Shimada T. A new strategy for large-scale preparation of high-titer recombinant adeno-associated virus vectors by using packaging cell lines and sulfonated cellulose column chromatography. Hum Gene Ther 1996; 7(4): 507–513, https://doi.org/10.1089/hum.1996.7.4-507.
15. Miyake K., Miyake N., Yamazaki Y., Shimada T., Hirai Y. Serotype independent method of recombinant adeno-associated virus (AAV) vector production and purification. J Nippon Med Sch 2012; 79(6): 394–402, https://doi.org/10.1272/jnms.79.394.
16. Shuvaev A.N., Horiuchi H., Seki T., Goenawan H., Irie T., Iizuka A., Sakai N., Hirai H. Mutant PKCγ in spinocerebellar ataxia type 14 disrupts synapse elimination and long-term depression in Purkinje cells in vivo. J Neurosci 2011; 31(40): 14324–14334, https://doi.org/10.1523/JNEUROSCI.5530-10.2011.
17. Safo P.K., Cravatt B.F., Regehr W.G. Retrograde endocannabinoid signaling in the cerebellar cortex. Cerebellum 2006; 5(2): 134–145, https://doi.org/10.1080/14734220600791477.
18. Hashimotodani Y., Ohno-Shosaku T., Kano M. Ca(2+)-assisted receptor-driven endocannabinoid release: mechanisms that associate presynaptic and postsynaptic activities. Curr Opin Neurobiol 2007; 17(3): 360–365, https://doi.org/10.1016/j.conb.2007.03.012.
19. Kano M., Ohno-Shosaku T., Hashimotodani Y., Uchigashima M., Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 2009; 89(1): 309–380, https://doi.org/10.1152/physrev.00019.2008.
20. Best A.R., Regehr W.G. Identification of the synthetic pathway producing the endocannabinoid that mediates the bulk of retrograde signaling in the brain. Neuron 2010; 65(3): 291–292, https://doi.org/10.1016/j.neuron.2010.01.030.
21. Gao Z., van Beugen B.J., De Zeeuw C.I. Distributed synergistic plasticity and cerebellar learning. Nat Rev Neurosci 2012; 13(9): 619–635, https://doi.org/10.1038/nrn3312.
22. Irie T., Matsuzaki Y., Sekino Y., Hirai H. Kv3.3 channels harboring a mutation of spinocerebellar ataxia type 13 alter excitability and induce cell death in cultured cerebellar Purkinje cells. J Physiol 2014; 592(Pt 1): 229–247, https://doi.org/10.1113/jphysiol.2013.264309.
23. Huda F., Konno A., Matsuzaki Y., Goenawan H., Miyake K., Shimada T., Hirai H. Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model. Molecular Therapy — Methods & Clinical Development 2014; 1: 14032, https://doi.org/10.1038/mtm.2014.32.
24. Hirai H., Taisuke M., Wataru K., Shinji M., Masayoshi M., Watanabe M., Yuzaki M. Rescue of abnormal phenotypes of the δ2 glutamate receptor-null mice by mutant δ2 transgenes. EMBO Reports 2005; 6(1): 90–95, https://doi.org/10.1038/sj.embor.7400312.
25. Vassileva G., Smeyne R.J., Morgan J.I. Absence of neuroanatomical and behavioral deficits in L7/pcp-2-null mice. Mol Brain Res 1997; 46(1–2): 333–337, https://doi.org/10.1016/s0169-328x(97)00081-8.
26. Barski J.J., Hartmann J., Rose C.R., Hoebeek F., Mörl K., Noll-Hussong M., De Zeeuw C.I., Konnerth A., Meyer M. Calbindin in cerebellar Purkinje cells is a critical determinant of the precision of motor coordination. J Neurosci 2003; 23(8): 3469–3477.
27. Finch E.A., Augustine G.J. Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature 1998; 396(6713): 753–756, https://doi.org/10.1038/25541.

Shuvaev A.N., Hirai Н. Experience of mGLuR1 Gene Therapy in Transgenic Models of SCA1 Mice. Sovremennye tehnologii v medicine 2016; 8(4): 143, https://doi.org/10.17691/stm2016.8.4.19