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

Abstract

Impairments in mitochondria and transcription are important factors in the pathogenesis of Huntington disease (HD), a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein. This study investigated the effect of different metabolic states and peroxisome proliferator-activated receptor γ (PPARγ) activation on sensitivity to cellular stressors such as H2O2 or thapsigargin in HD. Striatal precursor cells expressing wild type (STHdhQ7) or mutant huntingtin (STHdhQ111) were prepared in different metabolic conditions (glucose vs. pyruvate). Due to the fact that STHdhQ111 cells exhibit mitochondrial deficits, we expected that in the pyruvate condition, where ATP is generated primarily by the mitochondria, there would be greater differences in cell death between the two cell types compared to the glucose condition. Intriguingly, it was the glucose condition that gave rise to greater differences in cell death. In the glucose condition, thapsigargin treatment resulted in a more rapid loss of mitochondrial membrane potential (ΔΨm), a greater activation of caspases (3, 8, and 9), and a significant increase in superoxide/reactive oxygen species (ROS) in STHdhQ111 compared to STHdhQ7, while both cell types showed similar kinetics of ΔΨm-loss and similar levels of superoxide/ROS in the pyruvate condition. This suggests that bioenergetic deficiencies are not the primary contributor to the enhanced sensitivity of STHdhQ111 cells to stressors compared to the STHdhQ7 cells. PPARγ activation significantly attenuated thapsigargin-induced cell death, concomitant with an inhibition of caspase activation, a delay in ΔΨm loss, and a reduction of superoxide/ROS generation in STHdhQ111 cells. Expression of mutant huntingtin in primary neurons induced superoxide/ROS, an effect that was significantly reduced by constitutively active PPARγ. These results provide significant insight into the bioenergetic disturbances in HD with PPARγ being a potential therapeutic target for HD.

Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status

“…Our data suggest increasing cellular Mn burden results in a corresponding induction of ribulose 5-phosphate, an effect that was exaggerated in HD striatal cells relative to control. This finding corroborates previous studies that demonstrate HD striatal cell impairments in mitochondrial dynamics and energetics 51, 52 . The genotype-dependent difference was apparent only at the cytotoxic 125µM Mn exposure, while increasing cellular Mn burden from vehicle to 31µM does not significantly increase ribulose 5-phosphate levels.…”

Rosiglitazone activation of PPARγ-dependent signaling is neuroprotective in mutant huntingtin expressing cells

“…Napolitano and colleagues (2011) demonstrated that pioglitazone has useful effects on mitochondrial dysfunction by interfering with the NF-κB signaling cascade, which is involved in the 3 nitropropionic acid model of HD in primary striatal cells [42]. Another study described that the metabolic condition determines sensitivity to cellular stress in HD, demonstrating that STHdh Q111 cells exhibited higher superoxide and ROS, an effect that was distinctly reduced by constitutively active PPARγ with rosiglitazone [43]. We previously reported that PPARγ played a major function in the pathogenesis of HD, and demonstrated that TZD and rosiglitazone modulated energy deficiency in the striatum of R6/2 mice [23].…”

“…Several studies also implicate PPARγ activation for the neuroprotective effects of rosiglitazone and pioglitazone in HD [22,[41][42][43]. Importantly, PPARγ mediated increases in anti-apoptotic Bcl-2 protein expression in PC12 cells protects against apoptosis [76].…”

PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease

“…In striatal cells in culture expressing mutant huntingtin STHdh(Q111), rosiglitazone increased mitochondrial biogenesis and protected against calcium dependent (thapsigargin-induced) mitochondrial dysfunction [128]. Similarly, in cultured rat primary cortical neurons expressing mutant huntingtin STHdh(Q111), PPARγ activation by rosiglitazone significantly attenuated thapsigargin-induced cell death, concomitant with reduced caspase activation, a delay in the loss of ΔΨ m , and a reduction of ROS generation [80]. In addition, a reduction in mitochondrial mass associated with the expression of mutant huntingtin in N2A cells, was rescued by rosiglitazone [29].…”