Mitochondrial calcium uptake capacity as a therapeutic target in the R6/2 mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is an incurable autosomal-dominant neurodegenerative disorder initiated by an abnormally expanded polyglutamine domain in the huntingtin protein. It is proposed that abnormal mitochondrial Ca2+ capacity results in an increased susceptibility to mitochondrial permeability transition (MPT) induction that may contribute significantly to HD pathogenesis. The in vivo contribution of these hypothesized defects remains to be elucidated. In this proof-of-principle study, we examined whether increasing mitochondrial Ca2+ capacity could ameliorate the well-characterized phenotype of the R6/2 transgenic mouse model. Mouse models lacking cyclophilin D demonstrate convincingly that cyclophilin D is an essential component and a key regulator of MPT induction. Mitochondria of cyclophilin D knockout mice are particularly resistant to Ca2+ overload. We generated R6/2 mice with normal, reduced or absent cyclophilin D expression and examined the effect of increasing mitochondrial Ca2+ capacity on the behavioral and neuropathological features of the R6/2 model. A predicted outcome of this approach was the finding that cyclophilin D deletion enhanced the R6/2 brain mitochondria Ca2+ capacity significantly. Increased neuronal mitochondrial Ca2+ capacity failed to ameliorate either the behavioral and neuropathological features of R6/2 mice. We found no alterations in body weight changes, lifespan, RotaRod performances, grip strength, overall activity and no significant effect on the neuropathological features of R6/2 mice. The results of this study demonstrate that increasing neuronal mitochondrial Ca2+-buffering capacity is not beneficial in the R6/2 mouse model of HD.

Metabolic State Determines Sensitivity to Cellular Stress in Huntington Disease: Normalization by Activation of PPARγ

“…These results suggest that the protective effect of RSG and the higher susceptibility of STHdh Q111 cells to TG may not be related to mPTP. Similarly, a recent study using R6/2 mice crossed with CypD knockout mice demonstrated that the deletion of CypD in the R6/2 mice resulted in enhanced mitochondrial Ca 2+ buffering but did not show any improvement in the pathogenic symptoms or a delay in disease progression [45]. Further, RSG has been reported to protect cells against stresses by upregulation of PPARγ and Bcl-2, an anti-apoptotic protein that has been shown to be implicated with HD [14], [46].…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…This idea was reinforced by the fact that CypD is upregulated in Huntington's patients and that this upregulation increased as Huntington's disease progressed (Shirendeb et al., 2011). However, other reports did not find such significant contribution of mPTP to mitochondrial injury in Huntington's disease, demonstrating that genetic inactivation of CypD does not modify the onset and the progression of the disease in mice (Brustovetsky et al., 2005; Pellman, Hamilton, Brustovetsky, & Brustovetsky, 2015; Perry et al., 2010). …”

Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells

“…HD is caused by an aberrant expansion of the CAG repeat domain within exon one of the huntingtin (htt) gene (Group 1993). At the cellular level mutant htt (mthtt) interferes with various functions including transcriptional regulation (Luthi-Carter, Hanson et al 2002; Hodges, Strand et al 2006; Bithell, Johnson et al 2009), the maintenance of calcium homeostasis (Perry, Tallaksen-Greene et al 2010; Giacomello, Hudec et al 2011), and synaptic physiology (Klapstein, Fisher et al 2001; Milnerwood and Raymond 2007; Cummings, Andre et al 2009). …”