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

Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration

“…Drugs that control Ca 2+ homeostasis may therefore be good therapeutic options. Support for this idea was shown in a mouse model of SCA28 (Maltecca et al, 2015). …”

New roles for mitochondrial proteases in health, ageing and disease

“…Respiratory deficiencies in yeast cells that lack the mAAA protease are caused by impaired processing of the ribosomal subunit MrpL32, resulting in defective mitochondrial translation 52 . Loss of the mammalian mAAA subunit AFG3L2 also causes a decrease in mitochondrial calcium uptake that is due to induced mitochondrial fragmentation triggered by processing of dynamin-like 120 kDa protein (OPA1) (see below) 53 . Furthermore, following the stress response, the iAAA YME1L1 subunit degrades mitochondrial import inner membrane translocase subunit TIM17A, thereby decreasing protein import into the mitochondrion 54 .…”

“…Recent studies using these mutant mice have also demonstrated the essential roles of the mAAA protease in neuro logical function and in offsetting cerebellar degeneration 140 . AFG3L2 is also crucial for mitochondrial protein synthesis and survival of Purkinje cells, and defects in this protease induce mitochondrial-mediated Purkinje dark cell degeneration, changes in mitochondrial transport and tau hyperphosphorylation, which has been implicate d in neurodegeneration and dementia 51,141,142,53 .…”

Mitochondrial Quality Control Proteases in Neuronal Welfare

“…These factors were related to the inability of the mitochondria to adapt to oxidative stress, which is confirmed by rescue of cells with antioxidants (Kondadi et al 2014). On a related note, Maltecca et al recently showed that synaptic glutamate clearance caused by administration of the antibiotic ceftriaxone to Afg3l2-deficient mice reduced Ca 2+ influx and improved ataxia-like symptoms observed in these animals (Maltecca et al 2015). …”