Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

J Clin Invest. 2015 Jan;125(1):263-74. doi: 10.1172/JCI74770. Epub 2014 Dec 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Dependent Proteases / genetics
  • ATP-Dependent Proteases / metabolism
  • ATPases Associated with Diverse Cellular Activities
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling
  • Ceftriaxone / pharmacology
  • Ceftriaxone / therapeutic use
  • Dendrites / metabolism
  • Dendrites / pathology
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Humans
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Psychomotor Performance
  • Purkinje Cells / physiology*
  • Spinocerebellar Ataxias / congenital
  • Spinocerebellar Degenerations / drug therapy
  • Spinocerebellar Degenerations / metabolism*

Substances

  • Ceftriaxone
  • ATP-Dependent Proteases
  • Afg3l2 protein, mouse
  • ATPases Associated with Diverse Cellular Activities
  • Calcium

Supplementary concepts

  • Spinocerebellar ataxia 28