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  Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

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.

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Genre: Journal Article
Alternative Title : The Journal of Clinical Investigation

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 Creators:
Maltecca, Francesca, Author
Baseggio, Elisa, Author
Consolato, Francesco, Author
Mazza, Davide, Author
Podini, Paola, Author
Young Jr., Samuel M.1, Author
Drago, Ilaria, Author
Bahr, Ben A., Author
Puliti, Aldamaria, Author
Codazzi, Franca, Author
Quattrini, Angelo, Author
Casari, Giorgio, Author
Affiliations:
1Max Planck Florida Institute for Neuroscience, Max Planck Society, One Max Planck Way, Jupiter FL 33458, USA, ou_1950288              

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 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.

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 Dates: 2015
 Publication Status: Published in print
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Title: The Journal of Clinical Investigation
  Alternative Title : J Clin Invest
Source Genre: Journal
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Pages: - Volume / Issue: 125 (1) Sequence Number: - Start / End Page: 263 - 274 Identifier: ISBN: 0021-9738