1. Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model
- Author
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Ben A. Bahr, Francesca Maltecca, Ilaria Drago, Elisa Baseggio, Samuel M. Young, Francesco Consolato, Giorgio Casari, Aldamaria Puliti, Franca Codazzi, Angelo Quattrini, Paola Podini, Davide Mazza, Maltecca, Francesca, Baseggio, E, Consolato, F, Mazza, D, Podini, P, Young SM, Jr, Drago, I, Bahr, Ba, Puliti, A, Codazzi, F, Quattrini, A, and Casari, GIORGIO NEVIO
- Subjects
Pathology ,medicine.medical_specialty ,Ataxia ,Drug Evaluation, Preclinical ,Mice, Transgenic ,Biology ,Mitochondrion ,Transgenic ,Mice ,Purkinje Cells ,ATP-Dependent Proteases ,medicine ,Animals ,Humans ,Spinocerebellar Ataxias ,Calcium Signaling ,Calcium ,Ceftriaxone ,Dendrites ,Disease Models, Animal ,Mice, Inbred BALB C ,Mitochondria ,Psychomotor Performance ,Spinocerebellar Degenerations ,Inbred BALB C ,Calcium signaling ,Animal ,Glutamate receptor ,Depolarization ,General Medicine ,medicine.disease ,Preclinical ,Cell biology ,Metabotropic glutamate receptor ,Disease Models ,Spinocerebellar ataxia ,Metabotropic glutamate receptor 1 ,ATPases Associated with Diverse Cellular Activities ,Drug Evaluation ,medicine.symptom ,Research Article - 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.
- Published
- 2015