Natural Product Compounds from Plants in Neurodegenerative Diseases
Namrita Lall in Medicinal Plants for Cosmetics, Health and Diseases, 2022
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).
The nervous system and the eye
C. Simon Herrington in Muir's Textbook of Pathology, 2020
In this autosomal dominant disorder progressive dementia is accompanied by involuntary choreiform movements. Huntington's disease (HD) usually begins in the 40 or 50 s and has an incidence of about 47 per 100,000 population. The cause of Huntington's disease is an increased number of trinucleotide repeats (CAG), which encode the amino acid glutamine, in the huntingtin gene on chromosome 4. The normal gene contains 9–37 CAG repeats, whereas in patients with HD there may be in the region of 37–100. This knowledge allows prediction of susceptibility in as yet unaffected family members and antenatal testing. The mutation is unstable and the phenomenon of anticipation may occur: in succeeding generations the disease occurs with an earlier age of onset and increasing severity as the number of CAG repeats increases. On examination of the brain the most striking feature is selective atrophy of the caudate nucleus (Figure 12.35). There may also be cortical atrophy. Histological examination reveals loss of small neurons and gliosis in the caudate nuclei with variable involvement of other nuclei in the basal ganglia and the cerebral cortex. The huntingtin protein produced in HD is abnormal, containing a long chain of glutamine amino acid residues as a consequence of the CAG repeats in the huntingtin gene, and accumulates as dot-like intranuclear inclusions.
Vitamin C Alimentation via SLC Solute Carriers
Qi Chen, Margreet C.M. Vissers in Vitamin C, 2020
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.
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.
Emerging therapeutics in Huntington’s disease
Published in Expert Opinion on Emerging Drugs, 2021
The huntingtin gene is located on chromosome 4 and involves a CAG trinucleotide repeat expansion in the gene’s first exon. The gene mutation is fully penetrant in individuals who carry greater than 39 CAG repeats. Patients with 36–39 repeats may or may not develop manifestations of HD (i.e. this number of repeats is not fully penetrant). Some patients with this number of repeats may develop motor and behavioral symptoms of HD, though others with the same number of repeats may not. The wild-type gene contains 35 or fewer repeats and confers no signs or symptoms of HD and a normal life span. The CAG expansion is unstable, meaning the number of repeats can increase when passed on to subsequent generations, particularly when passed paternally. This leads to disease with a younger age of onset. This concept is termed anticipation. The wild-type huntingtin gene is thought to have important cellular functions involving embryonic development, protein scaffolding, transcription regulation and synaptic connections [5]. The mutant huntingtin gene (mhtt) is transcribed and subsequently translated into mutant huntingin protein (mHTT). There is ongoing discussion and research about the pathogenesis of HD related to mHTT. The exact mechanism by which mHTT causes HD remains unknown but is thought to be related to a toxic gain of function as opposed to loss of function of the normal protein. Mutated huntingtin protein aggregates forming intranuclear inclusions have been found in the cortex, hippocampus and striatum of patients with HD. These inclusions themselves may be neurotoxic, but the exact cause of pathogenicity in HD is unknown and is still being investigated [6].
Related Knowledge Centers
- Protein
- Gene
- Mutation
- Huntington's Disease
- Glutamine
- Wild Type
- Dominance
- Genetic Disorder
- Neuron
- Apoptosis