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Neurological Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
This is an autosomal dominant condition resulting from an expanded trinucleotide repeat in the Huntingtin gene. Accumulation of the Huntingtin gene product in intracellular inclusions disrupts cellular metabolism and leads to cell death, most marked in the striatum and the cortex. It causes chorea, fidgetiness, impaired judgement and impaired cognitive function.
Natural Product Compounds from Plants in Neurodegenerative Diseases
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Priya Darshani, Md TanjimAlam, Prem P. Tripathi, V.S. Pragadheesh
HD is a neurodegenerative genetic disorder caused by autosomal dominance mutation in either copy of the genes called huntingtin. It is a rare, inherited, autosomal-dominant neurodegenerative disease that progresses to death in 10–30 years after its onset. It involves a spectrum of motor, cognitive and psychiatric impairments (Rieux et al., 2020). The huntingtin gene provides genetic information to the huntingtin protein. It is associated with the accumulation of a mutant huntingtin protein (mHTT), which consists of an extended polyglutamine (poly Q) stretch. It provokes pathological changes in both the central and peripheral nervous systems. mHTT is formed due to the expansion of CAG (cytosine-adenine-guanine) triplet repeats in the gene coding for huntingtin protein. However, the exact pathophysiological mechanism remains unknown to date (Jimenez-Sanchez et al., 2016).
Vitamin C Alimentation via SLC Solute Carriers
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Damian Nydegger, Gergely Gyimesi, Matthias A. Hediger
Huntington disease is a genetic disorder caused by a mutation of the gene coding for Huntingtin. Mutation of Huntingtin leads to involuntary movements, cognitive deterioration, dementia, and weight loss. This protein is responsible for the intracellular trafficking of vesicles, organelles, and proteins to the cell surface. In immortalized striatal neurons expressing mutated Huntingtin, it was shown that SVCT2 is no longer able to translocate to the plasma membrane in response to increased extracellular ascorbic acid levels. Huntingtin is known to be associated to vesicles and microtubules, suggesting a role of this protein in the transport of SVCT2-containing vesicles, in order to deliver SVCT2 to the plasma membrane of neurons. Huntington disease is connected to increased oxidative damage in lipids, proteins, and DNA, highlighting the protecting role of vitamin C as an antioxidant in neurons. These results also highlight the possible role of SVCT2 in other neurodegenerative diseases such as Alzheimer and Parkinson diseases [71].
Animal models of Huntington’s disease and their applicability to novel drug discovery and development
Published in Expert Opinion on Drug Discovery, 2023
Shubham Upadhayay, Sumit Jamwal, Puneet Kumar
Huntington’s disease (HD) is a severe neurodegenerative disorder instigated by a mutation in the huntingtin (Htt) gene that leads to the production of mutant huntingtin protein (mHTT), whose aggregates degenerate the GABAergic medium spiny neurons (MSNs) in the basal ganglia, resulting in increased involuntary movements [1]. According to optimistic estimates, about 2.7 million people worldwide suffer from HD-like clinical manifestations, including jerking movements, fecal tenesmus, cognitive impairment, apathy, and difficulty in performing routine activities [2]. The key pathogenic processes involved in neuronal degeneration in HD include oxidative stress, mitochondrial dysfunction, apoptosis, neuroinflammation, transcriptional regulation, altered neurotransmitter signaling, and mitochondrial biogenesis [1,3]. The prevalence of HD increases day by day as a meta-analysis study of 2011 to 2022 suggests that the count of HD patients reaches to 4.88 per 100,000 patients when compared to the prevalence in 1985 to 2010, i.e. 2.71 per 100,000 patients, indicating that the incidence of HD gets doubled in 10 years [4]. Only two FDA-approved drugs (tetrabenazine and deutetrabenazine) are available in the market, which provides symptomatic relief with untoward side effects [5]. Therefore, there is an urgent need to discover newer therapies that could effectively help in the management of this disease.
Effect of nutrition on neurodegenerative diseases. A systematic review
Published in Nutritional Neuroscience, 2021
Vittorio Emanuele Bianchi, Pomares Fredy Herrera, Rizzi Laura
Huntington's disease (HD) is s a progressive brain disorder caused by the expansion of a CAG (trinucleotide cytosine-adenine-guanine) repeat in the huntingtin gene. This mutation results in the production of the polyglutamine-expanded huntingtin protein (mHtt), leading to involuntary choreiform movements, cognitive impairment, and neuropsychiatric symptoms one of the most devastating genetic neurodegenerative disorders with no valid medical therapy [40]. The exact mechanism of the disease progression has not been elucidated. mHtt causes transcriptional dysregulation, which can lead to neuronal cell death in the brain [41]. Many defects in mitochondria have been observed in various HD mouse models [42], cell models, and patients, and the striatum is the brain region that is particularly vulnerable to mitochondrial impairment [43]. Alteration of energy metabolism may be involved in the pathogenesis of HD. It was shown that HD patients with a higher BMI have a slower progression of the disease [44].
AAV5-miHTT gene therapy for Huntington disease: lowering both huntingtins
Published in Expert Opinion on Biological Therapy, 2020
Melvin M. Evers, Pavlina Konstantinova
Lowering mutant huntingtin protein levels would prevent downstream toxic effects, but complete suppression of huntingtin may not be desirable since wild-type huntingtin is highly conserved and has numerous important cellular functions, such as transcriptional regulation, axonal trafficking, endocytosis, mitochondrial function, and cellular stress responses, extensively reviewed in [15]. Knock-out of the homologous Htt mouse gene was found to be early embryonically lethal [16–18]. Furthermore, wild-type huntingtin protein is reported to act as a protector of brain cells from apoptotic stimuli [19] and is required in adult neurons as Htt inactivation in adult mice was shown to result in progressive neurodegeneration [20]. In a recent study in adult mice, total depletion of huntingtin in the brain was well tolerated at all ages with no motor problems or bodyweight issues [21]. Other studies have shown that total knock-down in the striatum and cerebral cortex is well tolerated up to 14 months after conditional knock-out [22]. The same study showed that the thalamus and cerebellum are more vulnerable to total huntingtin elimination. This would suggest that if a mutant allele-specific approach is not feasible, an approach to nonselectively lower huntingtin protein most prominently targeted at the striatum and cortex would be favored whereas lowering of other brain structures and peripheral organs should be limited.