Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model.
J Clin Invest
; 125(1): 263-74, 2015 Jan.
Article
in En
| MEDLINE
| ID: mdl-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 Ca²âº peaks, resulting in enhanced cytoplasmic Ca²âº concentrations, which subsequently triggers PC-DCD. This Ca²âº-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 Ca²âº influx in PCs and reversed the ataxic phenotype. Moreover, administration of the ß-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca²âº 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 Ca²âº 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Purkinje Cells
/
Spinocerebellar Degenerations
/
Calcium
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Clin Invest
Year:
2015
Document type:
Article