Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model.

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 ?-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.

SUBMITTER: Maltecca F 

PROVIDER: S-EPMC4382234 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature