VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Abstract

It is becoming increasingly evident that mitochondria dysfunction plays an important role in pathogenesis of Huntington's disease (HD). However, the underlying mechanism is still needs to be explained. The crucial aspect of the explanation is to indicate the upstream events in mitochondria dysfunction that could contribute to HD. In the review we propose the defect of voltage-dependent anion-selective channel (VDAC), as a causative event in HDrelated mitochondria dysfunction. Thus, we propose to consider VDAC as a crucial element in HD etiology and consequently as a reasonable target for therapeutic interventions in HD, based on developing novel therapeutic strategies eliminating mitochondria dysfunction.Keywords: Huntington's disease; VDAC; Mitochondria; Therapy Huntington's DiseaseHuntington's disease (HD) is a progressive and fatal neurodegenerative disease with a prevalence of about 5-10/100 000. Clinically, the disease is characterized by progressive chorea (involuntary dance-like movements), rigidity, weight loss, dementia, seizures and psychiatric disturbances such as depression, withdrawal and irritability. These symptoms including cognitive deterioration, psychiatric disturbances, and movement disorders result from a selective and continuous loss of neurons from the striatum and deep layers of the cerebral cortex although other brain regions such as thalamus and subthalamic nucleus are also affected [1][2][3]. Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al. [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades. Thus, a new therapeutic approach involving new potential targets and to start before the symptomatic stage could contribute to HD treatment to be more specific and effective. This, in turn, requires further studies concerning molecular mechanisms underlying HD.The genetic hallmark of HD is an expansion of an unstable trinucleotide CAG repeat region within the first exon of the gene encoding the protein Huntington (Htt). This results in synthesis of its mutant form (mHtt) containing more than 36 glutamine residues at N terminus although the possible contribution of mHtt encoding mRNA, i.e. toxic mRNA in HD etiology has also been suggested [7]. HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12]. Importantly, Htt expression in diffe...

The Association of VDAC with Cell Viability of PC12 Model of Huntington’s Disease

“…Importantly, the interaction was also reported for human VDAC isoforms [e.g., Kaltenbach et al (22); see also ]. Thus, one could assume that the possible upstream events in mitochondria dysfunction resulting in HD may include VDAC (16). …”

“…They address mHtt effects on mitochondrial bioenergetics and biogenesis, protein import complex assembly, fission and fusion, mitochondrial transport including Ca 2+ and metal homeostasis, and the degradation of damaged mitochondria via autophagy (mitophagy). Simultaneously, it is also evident that voltage-dependent anion-selective channel (VDAC), regarded as a dynamic regulator, or even governor, of mitochondrial functions, contributes to affected phenomena directly or by interacting with the involved proteins [e.g., Colombini (11); Mannella and Kinnally (12); Shoshan-Barmatz et al (13); Maldonado and Lemasters (14); Martel et al (15); Karachitos et al (16)].…”