Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Maltecca, Francesca; Baseggio, Elisa; Consolato, Francesco; Mazza, Davide; Podini, Paola; Young Jr., Samuel M.; Drago, Ilaria; Bahr, Ben A.; Puliti, Aldamaria; Codazzi, Franca; Quattrini, Angelo; Casari, Giorgio

doi:10.1172/JCI74770

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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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Item Permalink: https://hdl.handle.net/21.11116/0000-0003-D557-B Version Permalink: https://hdl.handle.net/21.11116/0000-0003-D558-A

Genre: Journal Article

Alternative Title : The Journal of Clinical Investigation

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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

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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: Date issued: 2015

Publication Status: Issued

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Identifiers: URI: http://www.jci.org/articles/view/74770
DOI: 10.1172/JCI74770

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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