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Huntington's disease (HD) is an autosomal inherited progressive neurodegenerative disorder which is caused by the CAG trinucleotide repeat in the huntingtin gene. The mutation induces mitochondrial dysfunction in neurons, which leads to striatal neuronal loss. The efficacy of the available therapies is limited, thus acquisition of more data about the pathomechanism of HD and development of new strategies is urgent. Sirtuins (Sirt1-7) belong to the histone deacetylase family, and interestingly they have been associated with HD, however, their role in HD is still not fully understood. To clarify the role of sirtuins in HD, we utilized a 3-nitropropionic acid (3-NP) induced HD model and assessed alterations in gene expression using RT-PCR. Moreover, we studied the extension of neurodegeneration in the striatum, and behavioural changes. Furthermore, we involved Sirt3 knockout (Sirt3KO) mice to investigate the impact of Sirt3 deficiency in the expression of the other sirtuins. Our results showed that with 3-NP treatment, the mRNA level of Sirt2,5,7 changed significantly in wild-type (WT) mice, whereas in Sirt3KO animals there was no change. Interestingly, Sirt3 deficiency did not exacerbate 3-NP-mediated striatal neuronal loss, while Sirt3KO animals showed higher mortality than WT littermates. However, the absence of Sirt3 did not affect the behaviour of animals. Finally, we demonstrated that the changes in the expression of sirtuins are age- and sex- dependent. According to our findings, there is evidence that Sirt3 has a major impact on the regulation of other sirtuin isoforms, survival and neuroprotection. However, this neuroprotective effect does not manifest in the behaviour., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Recent advances in therapeutic options may prevent deterioration related to Huntington's disease (HD), even at the pre-symptomatic stage. Be that as it may, a well-characterized patient population is essential for screening and monitoring outcome. Accordingly, the aim of this study was to describe the characteristics of a Hungarian subpopulation of HD patients and mutation carriers diagnosed at the University of Szeged., Methods: We conducted a search for International Classification of Diseases (ICD) code G10H0 in the local medical database for the period of 1 January 1998 to 31 December 2018., Results: We identified 90 HD cases (male: 45, female: 45) and 34 asymptomatic carriers (male: 15, female: 19). The median age of onset was 45 years (range: 16-79). There were 3 cases of juvenile onset (3.3%), and 7 of late disease onset (7.8%). The median repeat length was 43 (range: 36-70) for the pathological and 19 for the non-pathological alleles (range: 9-35). 17.5% of the pathological alleles were in the decreased penetrance range, while 7% of non-pathological alleles were intermediate., Conclusions: The genetic and clinical features of the population examined in the present study were in line with the previous Hungarian study, as well as with international literature. The exceptions were the higher ratio of reduced penetrance and intermediate alleles.

The potential role of Sirt1 and Sirt2 subtypes of Sirtuins (class III NAD + -dependent deacetylases) in the pathogenesis of Huntington's disease (HD) has been extensively studied yielding some controversial results. However, data regarding the involvement of Sirt3 and their variants in HD are considerably limited. The aim of this study was to assess the expression pattern of Sirt1 and three Sirt3 mRNA isoforms (Sirt3-M1/2/3) in the striatum, cortex and cerebellum in respect of the effect of gender, age and the presence of the transgene using the N171-82Q transgenic mouse model of HD. Striatal, cortical and cerebellar Sirt1-Fl and Sirt3-M1/2/3 mRNA levels were measured in 8, 12 and 16 weeks old N171-82Q transgenic mice and in their wild-type littermates. Regarding the striatum and cortex, the presence of the transgene resulted in a significant increase in Sirt3-M3 and Sirt1 mRNA levels, respectively, whereas in case of the cerebellum the transgene resulted in increased expression of all the assessed subtypes and isoforms. Aging exerted minor influence on Sirt mRNA expression levels, both in transgene carriers and in their wild-type littermates, and there was no interaction between the presence of the transgene and aging. Furthermore, there was no difference between genders. The unequivocal cerebellar Sirtuin activation with presumed compensatory role suggests that the cerebellum might be another key player in HD in addition to the most severely affected striatum. The mitochondrially acting Sirt3 may serve as an interesting novel therapeutic target in this deleterious condition.

Introduction: Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder. Despite the severe motor, psychiatric and cognitive symptoms and the great socioeconomic burden caused by the disease, available treatment is mainly symptomatic. The kynurenine pathway (KP) is the main metabolic route of tryptophan degradation, in the course of which several neuroactive compounds are generated. The imbalance of the neurotoxic and neuroprotectant metabolites can lead to excitotoxicity and overproduction of reactive oxygen species, which both contribute to the progression of HD. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme of the KP that has various immune modulatory roles. Areas covered: Current knowledge of the involvement of KP in HD pathogenesis with a particular focus on IDO1. By reviewing the diverse roles of the enzyme in kynurenine production, immune modulation, and serotonin metabolism, we elucidate the factors that make this enzyme a therapeutic target. Expert opinion: Due to the complexity of HD and the various effects that IDO1 exerts, targeting this enzyme, while highly profitable, may be a great challenge. Through IDO1 activity, neurodegeneration, inflammatory processes and depressive symptoms, often related to HD, can be modulated. Ongoing trials of IDO1 inhibitors in other areas of medicine offer advantages for initiating approaches toward this enzyme as a therapeutic target.

Huntington's disease is an autosomal dominant progressive neurodegenerative disease, which results in a decreased quality of life and an early death. A high prevalence of vitamin D deficiency was first described in a 2013 study in patients with manifest Huntington's disease, where serum vitamin D level was found to be associated with motor capabilities of the patients. Our objective was to investigate the effect of a high-dose vitamin D3 supplementation on a transgenic mouse model of Huntington's disease. Our study was performed on N171-82Q Huntington's disease transgenic mice in age- and gender-matched groups. We collected data on the motor state and survival of the mice. The results demonstrate that though vitamin D3 had no effect on the motor performance of transgenic mice, but significantly increased the lifespan of transgenic animals (Kaplan-Meier survival curves: vehicle-supplemented group: 73 (67-94) days vs. vitamin D3-supplemented group: 101 (74-109) days, p=0.048 Mantel-Cox log rank test). Further investigations are needed to determine whether a neuroprotective or a general corroborative effect of vitamin D leads to the measured effect. Our findings support the potential influence of vitamin D deficiency on the disease course and propose that vitamin D may be an effective supplementary treatment to beneficially influence clinical features of Huntington's disease.

Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1 alpha (PGC-1α) is involved in the regulation of mitochondrial biogenesis, respiration, and adaptive thermogenesis. The full-length PGC-1α (FL-PGC-1α) comprises multiple functional domains interacting with several transcriptional regulatory factors such as nuclear respiratory factors, estrogen-related receptors, and PPARs; however, a number of PGC-1α splice variants have also been reported recently. In this study, we examined the expression levels of FL-PGC-1α and N-truncated PGC-1α (NT-PGC-1α), a shorter but functionally active splice variant of PGC-1α protein, in N171-82Q transgenic and 3-nitropropionic acid-induced murine model of Huntington's disease (HD). The expression levels were determined by RT-PCR in three brain areas (striatum, cortex, and cerebellum) in three age groups (8, 12, and 16 weeks). Besides recapitulating prior findings that NT-PGC-1α is preferentially increased in 16 weeks of age in transgenic HD animals, we detected age-dependent alterations in both models, including a cerebellum-predominant upregulation of both PGC-1α variants in transgenic mice, and a striatum-predominant upregulation of both PGC-1α variants after acute 3-nitropropionic acid intoxication. The possible relevance of this expression pattern is discussed. Based on our results, we assume that increased expression of PGC-1α may serve as a compensatory mechanism in response to mitochondrial damage in transgenic and toxin models of HD, which may be of therapeutic relevance.

Background: Huntington's disease is a progressive neurodegenerative disease, genetically determined by CAG trinucleotide expansions in the IT15 gene. The onset of the symptoms is related to the number of CAG triplets. Because the patients are asymptomatic in the early phase of the disease, in vivo biomarkers are needed to follow up the reurodegeneration and to test putative neuroprotective approaches. One such promising biomarker is the diffusion MRI measured microstructural alteration of the white matter., Methods: Seven presymtomatic, mutation carriers and ten age-matched healthy controls were included in the study. Diffusion parameters were compared between groups and correlated with measures describing neurodegeneration. In order to reduce the possible misregistration bias due to atrophy the analysis was restricted to the core of each fibre bundles as defined by maximal fractional anisotropy (Tract-Based Spatial Statistics)., Results: Decreased fractional anisotropy, along with increased mean, parallel and perpendicular diffusivity was found in white matter tracts, mainly in the corpus callosum. An inverse correlation was detected between the fractional anisotropy and neurodegeneration score (derived from the number of CAG triplets and the patient age) from the areas of the left precentral gyrus, frontal lobe, corpus callosum and the capsula extrema. Altered diffusion parameters are promising biomarkers of the neurodegeneration in Huntington's disease.

A mitochondrial dysfunction causes an abatement in ATP production, the induction of oxidative damage and the propagation of cell death pathways. It is additionally closely related to both glutamate excitotoxicity and neuroinflammation. All of these interconnected aspects of a cellular dysfunction are involved in the pathogenesis of numerous neurological disorders, including those with an acute (e.g. ischemic stroke) or a chronic (e.g. Huntington's disease) onset. Both acute and chronic neurodegenerative disorders have been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism in the pathogenesis of the disease. As regards neuroactive compounds featuring in the pathway, quinolinic acid is a specific agonist of N-methyl-d-aspartate receptors, and a potent neurotoxin with additional and marked free radical-producing and lipid peroxidation-inducing properties. The toxic effects of 3-hydroxy-L-kynurenine are mediated by free radicals. Besides the possibility of increasing brain kynurenic acid concentrations, L-kynurenine may have vasoactive properties, too. Kynurenic acid has proven to be neuroprotective in several experimental settings, but in consequence of its pharmacokinetic properties it is not applicable as systemic administration in human cases. The aim of this short review is to emphasize the common features of cerebral ischemia and Huntington's disease and to highlight therapeutic strategies targeting the kynurenine pathway., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Huntington's disease (HD) is a progressive neurodegenerative disorder, the pathomechanism of which is not yet fully understood. Excitotoxicity is known to be involved in the development of HD and antiglutamatergic agents may, therefore, have beneficial neuroprotective effects. One of these agents is the tryptophan metabolite kynurenic acid (KYNA), which is an endogenous NMDA receptor antagonist. However, its pharmacological properties rule out its systemic administration in CNS disorders. We have tested a novel KYNA analogue, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride, in the N171-82Q transgenic mouse model of HD. The analogue exhibited several significant effects: it prolonged the survival of the transgenic mice, ameliorated their hypolocomotion, prevented the loss of weight and completely prevented the atrophy of the striatal neurons. The beneficial effects of this KYNA analogue are probably explained by its complex anti-excitotoxic activity. As it did not induce any appreciable side-effect at the protective dose applied in a chronic dosing regime in this mouse model, it appears worthy of further thorough investigations with a view to eventual clinical trials.

Huntington's disease (HD) is one of the chronic devastating neurodegenerative disorders. The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of gamma-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by multifarious dysfunctional alterations including mitochondrial impairment. In the present study, the formation of inclusions caused by the mutation of huntingtin protein and its relationship with changes in energy metabolism and with pathological alterations were investigated both in transgenic and 3-nitropropionic acid-treated mouse models for HD. The HD and normal mice were characterized clinically; the affected brain regions were identified by immunohistochemistry and used for biochemical analysis of the ATP-producing systems in the cytosolic and the mitochondrial compartments. In both HD models, the activities of some glycolytic enzymes were somewhat higher. By contrast, the activity of glyceraldehyde-3-phosphate dehydrogenase was much lower in the affected region of the brain compared to that of the control. Paradoxically, at the system level, glucose conversion into lactate was enhanced in cytosolic extracts from the HD brain tissue, and the level of ATP was higher in the tissue itself. The paradox could be resolved by taking all the observed changes in glycolytic enzymes into account, ensuing an experiment-based detailed mathematical model of the glycolytic pathway. The mathematical modelling using the experimentally determined kinetic parameters of the individual enzymes and the well-established rate equations predicted the measured flux and concentrations in the case of the control. The same mathematical model with the experimentally determined altered V(max) values of the enzymes did account for an increase of glycolytic flux in the HD sample, although the extent of the increase was not predicted quantitatively. This suggested a somewhat altered regulation of this major metabolic pathway in HD tissue. We then used the mathematical model to develop a hypothesis for a new regulatory interaction that might account for the observed changes; in HD, glyceraldehyde-3-phosphate dehydrogenase may be in closer proximity (perhaps because of the binding of glyceraldehyde-3-phosphate dehydrogenase to huntingtin) with aldolase and engage in channelling for glyceraldehyde-3-phosphate. By contrast to most of the speculation in the literature, our results suggest 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 with pathological consequences.

Parkinson's disease (PD) and Huntington's disease (HD) are progressive chronic neurodegenerative disorders that are accompanied by a considerable impairment of the motor functions. PD may develop for familial or sporadic reasons, whereas HD is based on a definite genetic mutation. Nevertheless, the pathological processes involve oxidative stress and glutamate excitotoxicity in both cases. A number of metabolic routes are affected in these disorders. The decrease in antioxidant capacity and alterations in the kynurenine pathway, the main pathway of the tryptophan metabolism, are features that deserve particular interest, because the changes in levels of neuroactive kynurenine pathway compounds appear to be strongly related to the oxidative stress and glutamate excitotoxicity involved in the disease pathogenesis. Increase of the antioxidant capacity and pharmacological manipulation of the kynurenine pathway are therefore promising therapeutic targets in these devastating disorders. [ABSTRACT FROM AUTHOR]