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Journal Article

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

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Young Jr.,  Samuel M.
Max Planck Florida Institute for Neuroscience, Max Planck Society;

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Citation

Maltecca, F., Baseggio, E., Consolato, F., Mazza, D., Podini, P., Young Jr., S. M., et al. (2015). Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. The Journal of Clinical Investigation, 125(1), 263-274. doi:10.1172/JCI74770.


Cite as: http://hdl.handle.net/21.11116/0000-0003-D557-B
Abstract
Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the mitochondrial protease AFG3L2. The SCA28 mouse model, which is haploinsufficient for Afg3l2, exhibits a progressive decline in motor function and displays dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we determined that mitochondria in cultured Afg3l2-deficient PCs ineffectively buffer evoked Ca2+ peaks, resulting in enhanced cytoplasmic Ca2+ concentrations, which subsequently triggers PC-DCD. This Ca2+-handling defect is the result of negative synergism between mitochondrial depolarization and altered organelle trafficking to PC dendrites in Afg3l2-mutant cells. In SCA28 mice, partial genetic silencing of the metabotropic glutamate receptor mGluR1 decreased Ca2+ influx in PCs and reversed the ataxic phenotype. Moreover, administration of the β-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca2+ influx, improved ataxia-associated phenotypes in SCA28 mice when given either prior to or after symptom onset. Together, the results of this study indicate that ineffective mitochondrial Ca2+ handling in PCs underlies SCA28 pathogenesis and suggest that strategies that lower glutamate stimulation of PCs should be further explored as a potential treatment for SCA28 patients.