Mitochondrial and redox modifications in early stages of Huntington disease

Defects in mitochondrial function and mitochondrial-related redox deregulation have been attributed to Huntington disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. Thus, in the present study, we analyzed changes in mitochondrial function and overreduced states associated with production of reactive oxygen species (ROS) at early stages and along disease progression in vivo in the brain by positron emission tomography (PET) and in skin fibroblasts of premanifest/early and manifest HD patients, and in YAC128 transgenic mouse brain (striatum and cortex) at early-symptomatic (3 month-old, mo) and symptomatic (6 to 12 mo) stages. In vivo human and mouse brain PET imaging was assessed using [64Cu]-ATSM; analysis of oxygen consumption rates was assessed by Seahorse analysis, hydrogen peroxide levels were determined using fluorescent probes and mitochondrial morphology by transmission electron microscopy in human skin fibroblasts and mouse striatal and cortical isolated mitochondria. Premanifest and prodromal HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number, concomitantly with enhanced basal and maximal respiration, proton (H+) leak and increased hydrogen peroxide levels, the later progressing to advanced HD stage, in human fibroblasts. Mitochondria from fibroblasts of premanifest HD carriers also showed reduced roundness, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. Pre/early-symptomatic YAC128 mouse striatal, but not cortical, isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production along with increased complex II and III activities, enhanced mitochondrial hydrogen peroxide and roundness, as revealed by brain ultrastructure analysis, further presenting defects in Ca2+ handling, supporting increased striatal susceptibility in the YAC128 mouse model. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter extending over late disease stages.

Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice

Global manganese-responsive processes are suppressed in the YAC128 mouse model of Huntington's Disease (HD) compared to wild type (WT).

Latent Toxoplasma gondii infection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

Toxoplasma gondii causes a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra-cellular parasite cysts in brain. Despite life-long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection with Toxoplasma gondii suggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain of T. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild-type and HD mice were infected at 2-months of age. During the 10-month follow-up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD-infection interaction in mice that provides insights into the large variability of the human HD phenotype.