Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)263-274
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number1
DOIs
Publication statusPublished - Jan 2 2015

Fingerprint

Purkinje Cells
Ataxia
Glutamic Acid
Phenotype
Lactams
Metabotropic Glutamate Receptors
Ceftriaxone
Dendrites
Neurodegenerative Diseases
Organelles
Spinocerebellar ataxia 28
Buffers
Mitochondria
Peptide Hydrolases
Anti-Bacterial Agents
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Maltecca, F., Baseggio, E., Consolato, F., Mazza, D., Podini, P., Young, S. M., ... Casari, G. (2015). Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. Journal of Clinical Investigation, 125(1), 263-274. https://doi.org/10.1172/JCI74770

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. / Maltecca, Francesca; Baseggio, Elisa; Consolato, Francesco; Mazza, Davide; Podini, Paola; Young, Samuel M.; Drago, Ilaria; Bahr, Ben A.; Puliti, Aldamaria; Codazzi, Franca; Quattrini, Angelo; Casari, Giorgio.

In: Journal of Clinical Investigation, Vol. 125, No. 1, 02.01.2015, p. 263-274.

Research output: Contribution to journalArticle

Maltecca, F, Baseggio, E, Consolato, F, Mazza, D, Podini, P, Young, SM, Drago, I, Bahr, BA, Puliti, A, Codazzi, F, Quattrini, A & Casari, G 2015, 'Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model', Journal of Clinical Investigation, vol. 125, no. 1, pp. 263-274. https://doi.org/10.1172/JCI74770
Maltecca F, Baseggio E, Consolato F, Mazza D, Podini P, Young SM et al. Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. Journal of Clinical Investigation. 2015 Jan 2;125(1):263-274. https://doi.org/10.1172/JCI74770
Maltecca, Francesca ; Baseggio, Elisa ; Consolato, Francesco ; Mazza, Davide ; Podini, Paola ; Young, Samuel M. ; Drago, Ilaria ; Bahr, Ben A. ; Puliti, Aldamaria ; Codazzi, Franca ; Quattrini, Angelo ; Casari, Giorgio. / Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 1. pp. 263-274.
@article{2a4b2b42bfc241e29f0cc03f6067aecb,
title = "Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model",
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.",
author = "Francesca Maltecca and Elisa Baseggio and Francesco Consolato and Davide Mazza and Paola Podini and Young, {Samuel M.} and Ilaria Drago and Bahr, {Ben A.} and Aldamaria Puliti and Franca Codazzi and Angelo Quattrini and Giorgio Casari",
year = "2015",
month = "1",
day = "2",
doi = "10.1172/JCI74770",
language = "English",
volume = "125",
pages = "263--274",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

AU - Maltecca, Francesca

AU - Baseggio, Elisa

AU - Consolato, Francesco

AU - Mazza, Davide

AU - Podini, Paola

AU - Young, Samuel M.

AU - Drago, Ilaria

AU - Bahr, Ben A.

AU - Puliti, Aldamaria

AU - Codazzi, Franca

AU - Quattrini, Angelo

AU - Casari, Giorgio

PY - 2015/1/2

Y1 - 2015/1/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84920438196&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920438196&partnerID=8YFLogxK

U2 - 10.1172/JCI74770

DO - 10.1172/JCI74770

M3 - Article

C2 - 25485680

AN - SCOPUS:84920438196

VL - 125

SP - 263

EP - 274

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -