Mitochondrial alterations accompanied by oxidative stress conditions in skin fibroblasts of Huntington’s disease patients

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder manifesting as progressive impairment of motor function and different neuropsychiatric symptoms caused by an expansion of CAG repeats in huntingtin gene (HTT). Mitochondrial dysfunction and bioenergetic defects can contribute to the course of the disease, however, the molecular mechanism underlying this process is still largely unknown. In this study, we aimed to determine several mitochondrial parameters in HD fibroblasts and assess their relevance to the disease progression as well as to value mitochondrial pathology in peripheral cells as disease potential biomarker. We showed that HD fibroblasts demonstrate significantly lower growth rate compared to control fibroblasts despite the lack of cell cycle perturbations. In order to investigate mitochondrial contribution to cell growth differences between HD and healthy cells, we provided insight into various mitochondrial parameters. Conducted experiments have revealed a significant reduction of the ATP level in HD fibroblasts accompanied by a decrease in mitochondrial metabolic activity in relation to the cells from healthy donors. Importantly, there were no differences in the mitochondrial membrane potential (mtΔΨ) and OXPHOS complexes’ levels. Slightly increased level of mitochondrial superoxide (mt. O2•-), but not cytosolic reactive oxygen species (cyt. ROS), has been demonstrated. We have also observed significantly elevated levels of some antioxidant enzymes (SOD2 and GR) which may serve as an indicator of antioxidant defense system in HD patients. Thus, we suggest that mitochondrial alterations in skin fibroblasts of Huntington’s disease patients might be helpful in searching for novel disease biomarkers.

Genistein induces degradation of mutant huntingtin in fibroblasts from Huntington’s disease patients

“…The Unified Huntington’s Disease Rating Scale (UHDRS) was used to assess HD severity (Huntington Study Group 1996 ). Psychiatric features were assessed by the Clinical Global Impressions scale (CGI), and the functional assessment was measured by the Total Functional Capacity scale (TFC), as described previously (Jędrak et al 2018 ). Characteristics of the HD patient and control groups is presented in Table 1 .…”

“…Biopsies were taken from the forearm skin, and fibroblast lines were established as described previously (Jędrak et al 2017a , 2017b , 2018 ). Fibroblasts were cultured on 10-cm plates in DMEM (Thermo Fisher Scientific Inc., Paisley, UK) supplemented with 10% FBS (Thermo Fisher Scientific Inc., Paisley, UK) and 1% antibiotic/antimycotic solution (Sigma-Aldrich Co.…”

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

“…Non-transformed, patient-derived lines of MPS fibroblasts and HDFa were purchased from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research. In addition to HDFa, two other healthy fibroblast lines were employed in some RT-qPCR experiments (a line with no mutation detected, and an IDUA heterozygote); these lines were described previously [55,56] (all lines are characterized in Table 2). Fibroblasts used in this work had normal karyotypes.…”

Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases

“…Interestingly, these dysfunctions are closely connected to mitochondrial activity and to tissues with high mitochondrial density. Moreover, mitochondrial alterations are accompanied by oxidative stress in skin fibroblasts of patients [90]; additionally, the enzymatic activity of the Aco2, which catalyzes the conversion of citrate to isocitrate in the TCA cycle, is impaired in PBMCs of HD patients and PreHD carriers [91]. Authors suggest it as a potential biomarker to assess the disease status of both patients and carriers, being an easy and affordable non-invasive blood test in the clinical routine.…”