Journal article
Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model
The Journal of clinical investigation, Vol.125(1), pp.263-274
01/02/2015
DOI: 10.1172/JCI74770
PMCID: PMC4382234
PMID: 25485680
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 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 β-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.
Details
- Title: Subtitle
- Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model
- Creators
- Francesca Maltecca - Università Vita-Salute San Raffaele and Division of Genetics and Cell BiologyElisa Baseggio - Università Vita-Salute San Raffaele and Division of Genetics and Cell BiologyFrancesco Consolato - Università Vita-Salute San Raffaele and Division of Genetics and Cell BiologyDavide Mazza - Università Vita-Salute San Raffaele and Experimental Imaging Center, andPaola Podini - Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, ItalySamuel M Young - Research Group for Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USAIlaria Drago - Department of Biomedical Sciences, University of Padua, Padua, ItalyBen A Bahr - Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, North Carolina, USAAldamaria Puliti - Medical Genetics Unit, Istituto Giannina Gaslini, Genoa, Italy, and Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, ItalyFranca Codazzi - Cellular Neurophysiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, ItalyAngelo Quattrini - Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, ItalyGiorgio Casari - Università Vita-Salute San Raffaele and Division of Genetics and Cell Biology
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.125(1), pp.263-274
- DOI
- 10.1172/JCI74770
- PMID
- 25485680
- PMCID
- PMC4382234
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 01/02/2015
- Academic Unit
- Anatomy and Cell Biology; Iowa Neuroscience Institute; Otolaryngology
- Record Identifier
- 9984025311102771
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