Juvenile Huntington’s Disease Skin Fibroblasts Respond with Elevated Parkin Level and Increased Proteasome Activity as a Potential Mechanism to Counterbalance the Pathological Consequences of Mutant Huntingtin Protein

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disorder, caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin protein (Htt). Mitochondrial dysfunction and impairment of the ubiquitin-proteasome system (UPS) are hallmarks of HD neurons. The extraneural manifestations of HD are still unclear. We investigated the crosstalk between mitochondria and proteolytic function in skin fibroblasts from juvenile HD patients. We found reduced mitosis, increased cell size, elevated ROS and increased mitochondrial membrane potential in juvenile HD fibroblasts, while cellular viability was maintained. Mitochondrial OXPHOS analysis did not reveal significant differences compared to control. However, the level of mitochondrial fusion and fission proteins was significantly lower and branching in the mitochondria network was reduced. We hypothesized that juvenile HD fibroblasts counterbalance cellular damage and mitochondrial network deficit with altered proteasome activity to promote cell survival. Our data reveal that juvenile HD fibroblasts exhibit higher proteasome activity, which was associated with elevated gene and protein expression of parkin. Moreover, we demonstrate elevated proteasomal degradation of the mitochondrial fusion protein Mfn1 in diseased cells compared to control cells. Our data suggest that juvenile HD fibroblasts respond to mutant polyQ expansion of Htt with enhanced proteasome activity and faster turnover of specific UPS substrates to protect cells.

Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

“…XF Cell Mito Stress analyses were performed as described in [70], with modifications as follows. The mitochondrial inhibitors were applied at the following final concentrations: 2 µM oligomycin, 0.5 µM FCCP, and 1 µM antimycin-A.…”

“…The mitochondrial inhibitors were applied at the following final concentrations: 2 µM oligomycin, 0.5 µM FCCP, and 1 µM antimycin-A. Glycolysis stress was based on [70].…”

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

“…Glucose metabolism is decreased in affected brain regions of HD patients, and post-mortem brain samples exhibit decreased mitochondrial respiratory complex activity [166,167]. Moreover, mitochondrial malfunction occurs not only in affected brain regions but also in peripheral tissues such as skin fibroblasts derived from HD patients [168]. Mitochondria, isolated from lymphocytes of HD patients, exhibit decreased Ca 2+ -buffering capacity and altered mitochondrial membrane potential [169].…”

Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions

“…Concordantly, PINK1 overexpression in HD flies and ST Hdh Q111/Q111 cells proved to be protective in these models [ 312 ]. Moreover, juvenile HD fibroblasts showed increased Parkin levels [ 313 ]. Although there is some lack of information regarding the alterations in PINK1/Parkin-dependent mitophagy in HD, its activation may constitute an interesting therapeutic approach.…”