| First Author | Maltecca F | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 1 | Pages | 263-74 |
| PubMed ID | 25485680 | Mgi Jnum | J:219609 |
| Mgi Id | MGI:5621249 | Doi | 10.1172/JCI74770 |
| Citation | Maltecca F, et al. (2015) Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. J Clin Invest 125(1):263-74 |
| abstractText | 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 Ca(2)(+) peaks, resulting in enhanced cytoplasmic Ca(2)(+) concentrations, which subsequently triggers PC-DCD. This Ca(2)(+)-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 Ca(2)(+) influx in PCs and reversed the ataxic phenotype. Moreover, administration of the beta-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca(2)(+) 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 Ca(2)(+) 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. |
