Energy deficit in Huntington disease: why it matters

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models. Here we review the clinical, biochemical, and molecular evidence of an energy deficit in HD and discuss the mechanisms underlying mitochondrial and related alterations. IntroductionHuntington disease (HD) is an autosomal dominant neurodegenerative disease with age-dependent complete penetrance. HD is caused by a CAG repeat expansion in the first exon of the HTT gene that encodes huntingtin (Htt) (1, 2). Individuals who have 36 CAG repeats or more may develop the clinical symptoms and signs of HD, including neuropsychiatric, motor, and cognitive abnormalities that cause a progressive loss of functional capacity and shortened life span. The clinical features of HD typically emerge in adulthood between 30 and 50 years of age, after which the disease progresses relentlessly over the next 15-20 years (3). Presymptomatic testing - preceded by genetic counseling according to internationally accepted guidelines - allows an at-risk person to assess their genetic status and thus predict whether a carrier will develop HD before he or she shows clinical symptoms and signs. Of importance, the presymptomatic phase in HD provides a unique window for therapeutic intervention and neuroprotection.γ-Aminobutyric acid (GABAergic) medium spiny neurons of the striatum that contain enkephalin or substance P and project to the globus pallidus and substantia nigra are particularly vulnerable in HD and are key to the characteristic involuntary movements in this disease (4). The basis of the selective vulnerability of these neurons in HD remains elusive but may involve the reduced phosphorylation of Htt at serine 421 in the striatum (5), the specific localization of Rhes (Ras homolog enriched in striatum; a small guanine nucleotidebinding protein partner of Htt) to the striatum (6), and/or the preferential vulnerability of the striatum to mitochondrial dysfunction (7). However, the neuropathology is ultimately more widespread, affecting cortical neurons as well as the globus pallidus, substantia nigra, and brainstem. Understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability remains incomplete, but defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models (7,8). Here we provide an overview of clinical, biochemical, and molecular evidence of an energy deficit in HD, in both the brain and the peripheral organs. We also discuss the mechanisms underlying mitochondrial and related alterations in the context of both a

Consequences of Mitochondrial Dysfunction in Huntington's Disease and Protection via Phosphorylation Pathways

“…Moreover, reduced ATP production was observed in muscle of both presymptomatic and symptomatic HD patients (Lodi et al 2000). In fact, the onset of energyrelated manifestations at the presymptomatic stages of the disease, such as alterations in brain and muscle metabolism and weight loss, suggest that the energy deficit is likely to be an early phenomenon in the cascade of events leading to HD pathogenesis (Mochel and Haller 2011). Conversely, in HD N171-82Q mice model, increased glucose metabolism and ATP levels were found in brain tissue, suggesting that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level, leading to modified levels of various intermediary metabolites (Olah et al 2008).…”

Role of thiamine in Huntington’s disease pathogenesis: In vitro studies

“…Reduced ATP synthesis was found in immortalized HD striatal neuronal cell lines. 1 According Mochel et al, various mechanisms that underlie the energy deficit in HD phenotype have been proposed, including impaired oxidative phosphorylation, oxidative stress, impaired mitochondrial calcium handling, abnormal mitochondria trafficking, and deregulation of key factors of mitochondrial biogenesis or decreased glycolysis.…”

“…In fact, decreased ATP/ADP ratio was observed in HD patient-derived lymphoblastoid cell lines, which inversely correlated with the length of the mutant polyglutamine tract. 1 Mutant huntingtin was reported to affect the activity of mitochondrial complex I in the skeletal muscles of patients with HD. 3 Schapira mentioned that complex I deficiency had been found in HD platelets.…”

“…Evidence of enhanced oxidative stress in HD brains includes an increase in the accumulation of lipofuscin, a product of unsaturated fatty acids peroxidation or oxidative modification of proteins and lipids, also increased in HD brain and in animal models. 1 Gil-Mohapel et al in their review presented an overview of preclinical and clinical studies that have indicated a link between oxidative stress, neurodegeneration and cell death in HD. 5 Oxidative stress accompanies neurodegeneration and also causes abnormalities in thiamine-dependent processes.…”

Huntington’s disease modeling on HEK293 cell line

“…Вследствие возникновения этого тракта мутантный хантингтин перестает выполнять свою физиологическую функцию в клетках, а также нарушает работу и транспорт митохондрий (Orr et al, 2009;Mochel, Haller, 2011;Song et al, 2011), транскрипционный аппа-рат (Baydyuk, Xu, 2012;Seredenina, LuthiCarter, 2012) и другие клеточные процессы. В дальнейшем мутантный белок образует цитоплазматические агрегаты и ядерные включения в средних шипиковых нейронах стриатума, а на поздних стадиях заболевания -в клетках коры головного мозга (Labbadia, Morimoto, 2013).…”