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Experience of mGLuR1 Gene Therapy in Transgenic Models of SCA1 Mice

Experience of mGLuR1 Gene Therapy in Transgenic Models of SCA1 Mice

Shuvaev A.N., Hirai Н.
Keywords: spinocerebellar ataxia; SCA1; mGluR1; RORα.
СТМ, 2016, volume 8, issue 4, pages 143-156.

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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.

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Shuvaev A.N., Hirai Н. Experience of mGLuR1 Gene Therapy in Transgenic Models of SCA1 Mice. Sovremennye tehnologii v medicine 2016; 8(4): 143–156, http://dx.doi.org/10.17691/stm2016.8.4.19


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