TY - JOUR AU - Maltecca, Francesca AU - Baseggio, Elisa AU - Consolato, Francesco AU - Mazza, Davide AU - Podini, Paola AU - Young, Samuel M., Jr. AU - Drago, Ilaria AU - Bahr, Ben A. AU - Puliti, Aldamaria AU - Codazzi, Franca AU - Quattrini, Angelo AU - Casari, Giorgio T1 - Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model PY - 2015/01/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI74770 VL - 125 IS - 1 UR - https://doi.org/10.1172/JCI74770 SP - 263 EP - 274 PB - The American Society for Clinical Investigation ER -