Pathogenesis of Huntington’s Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies

Abstract

Background: Huntington’s disease is an inherited autosomal dominant trait neuro-degenerative disorder caused by changes (mutations) of a gene called huntingtin (htt) that is located on the short arm (p) of chromosome 4, CAG expansion mutation. It is characterized by unusual movements, cognitive and psychiatric disorders. Objective: This review was undertaken to apprehend biological pathways of Huntington’s disease (HD) pathogenesis and its management by nature-derived products. Natural products can be lucrative for the management of HD as it shows protection against HD in pre-clinical trials. Advanced research is still required to assess the therapeutic effectiveness of the known organic products and their isolated compounds in HD experimental models. Summary: Degeneration of neurons in Huntington’s disease is distinguished by progressive loss of motor coordination and muscle function. This is due to the expansion of CAG trinucleotide in the first exon of the htt gene responsible for neuronal death and neuronal network degeneration in the brain. It is believed that the factors such as molecular genetics, oxidative stress, excitotoxicity, mitochondrial dysfunction, neuroglia dysfunction, protein aggregation, and altered UPS leads to HD. The defensive effect of the natural product provides therapeutic efficacy against HD. Recent reports on natural drugs have enlightened the protective role against HD via antioxidant, anti-inflammatory, antiapoptotic, and neurofunctional regulation.

Role of Gut Microbiota in Neurological Disorders and Its Therapeutic Significance

“…The trinucleotide (cytosine–adenine–guanine, CAG) repeat in the Huntington (HTT) gene is expressed in the brain and an expanded CAG repeat length is the main cause of HD. In addition, other genetic factors such asoxidative stress, DNA damage, mitochondrial dysfunction, neuroglia dysfunction, and protein aggregation lead to HD [ 146 , 147 ]. Recent studies have suggested that HD may be associated with gut dysbiosis, which is caused by GIT dysfunction in an HD mouse model.…”

Mutant-Huntingtin Molecular Pathways Elucidate New Targets for Drug Repurposing

“…The most frequently, as shown by recent studies, transcriptional impairment affects neurotransmitter receptors, ion channels, and BDNF [11,12]. Aberrant huntingtin interacts with different transcription-regulating proteins (p53, CREB, CBP, and MSK-1, which control cell proliferation and DNA damage repair), PGC-1α, organelle and vesicle transporters, and dopamine 2 receptor-interacting proteins [13].…”

“…Mitochondria are a link between several pathological processes: disturbances of the electron transport chain, of metabolic processes, and of calcium homeostasis [11,12].…”

Failure to Thrive: Impaired BDNF Transport along the Cortical–Striatal Axis in Mouse Q140 Neurons of Huntington’s Disease

“…Huntington's disease (HD) is a progressive, dominantly inherited neurodegenerative disorder which is estimated to affect approximately one in every 10,000 people, with nearly 30,000 patients in the United States [1]. It is caused by the expansion of polyglutamine repeat (polyQ), encoded by the codon CAG, within the huntingtin (HTT) gene.…”

“…The use of protein overexpression has been widely used to examine transport [35][36][37]; however, these systems produce unavoidable artifacts that corrupt the endogenous nature of the neurite. The microfluidic chamber offers multiple advantages over other systems, the most important of which are: (1) ability to fluidically isolate distal dendrites from cell bodies; and (2) ability when coupled with exogenously applied ligands to allow for the observation of single-molecule transport in a physiologically relevant receptor/ligand setting. The separation of dendrites from neuronal soma using microfluidic devices has proven challenging but has been met with some success [38][39][40].…”