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.

Keywords: CAG expansion; Huntington’s disease (HD); huntingtin (htt); natural drugs; natural products; neurodegenerative disorder; pathogenesis.

Figure 1

CREB protein pathway in Normal individual and HD diseased patient. In normal individuals, CREB binding with CRE enables normal neuronal responses by activating a cascade of transcriptional factors (A) while in Huntington’s disease patients, due to mutant htt gene, CRE transcriptional cascade breaks, and there is no attachment of CBP and TAFII 130 with CRE. Pol II dispositioned (B).

Figure 2

NRSE mediated pathway in a normal individual and diseased patient. In normal individuals, transcription factor REST–NRSF binds to NRSEs in neuronal gene promoters such as in the brain-derived neurotrophic factor (BDNF) gene. By interacting with REST-NRSF in the cytoplasm and lowering its availability in the nucleus to bind to NRSE sites, wild-type htt maintains BDNF synthesis, which is a crucial survival factor for the striatal neurons that die in HD. In these circumstances, activators can bind to the BDNF promoter regions and then recruit the general transcriptional machinery and Pol II, promoting the transcription of BDNF. While in HD, REST-NRSF levels in the nucleus rise as a result of mutant htt’s failure to connect with REST-NRSF in the cytoplasm. In these circumstances, REST-NRSF binds to the NRSE with vigor and stimulates the recruitment of Sin3A-histone-deacetylase complexes (HDACs), which contain histone deacetylase activity for remodeling chromatin into a closed architecture and squelching BDNF transcription. REST stands for repressor-element-1 transcription factor. NRSE stands for neuron-restrictive silencer element.

Figure 3

Schematic of diverging pathways leading to the pathogenesis of HD. Here is the mechanism of pathogenesis, paying particular attention to those that are related to promising therapeutic targets. BDNF, Brain-derived neurotrophic factor; ROS, reactive oxygen species; NMDAR, N-methyl-D-aspartate receptor; UPS, Ubiquitin-protease System; NRSE, Neuron restrictive silencer elements; CRE, cAMP response element.

Figure 4

Ubiquitin-proteasome impairment in HD. In Normal individuals, Hsp70 and Hsp40 aid in transcriptional functions resulting in protein formation and aggregation and smooth functioning of mitochondria. However, in HD diseased patient mutant mhtt causes misfolding of protein aggregates and disrupts clearance pathways leading to mitochondrial dysfunction.

Figure 5

Steps in cellular pathogenesis of HD. (1). Huntingtin (htt), a freshly generated protein, is encouraged to fold into a native shape by the molecular chaperones Hsp70 and Hsp40. Wild-type htt is primarily cytoplasmic and likely participates in postsynaptic signaling, clathrin-mediated endocytosis, vesicle transport, cytoskeletal anchoring, or neuronal transport. HTT might enter the nucleus and influence the control of transcription; (2). In order to promote either their refolding or their ubiquitination (Ub) and subsequent demise by the 26S proteasome, chaperones can help recognize aberrant proteins. If chaperones are not present to rectify the incorrect folding of htt caused by the HD mutation, misfolded htt will accumulate in the cytoplasm. The HD mutation causes conformational alterations; (3). Alternately, mutant htt may also be cleaved by proteolysis, resulting in amino-terminal fragments that produce β-sheet structures; (4). Finally, cleaved N-terminal fragments, which may form soluble monomers, oligomers, or huge insoluble aggregates, or full-length mutant htt may cause toxicity. Mutant versions of htt may damage the ubiquitin-proteasome system (UPS) in the cytoplasm, causing a buildup of more improperly folded proteins; (5). These harmful proteins may also interfere with clathrin-mediated endocytosis and regular vesicle transport. Additionally, the presence of mutant htt may cause mitochondrial damage, which would directly or indirectly activate pro-apoptotic proteins and increase cellular toxicity as well as other negative effects; (6). The cell gathers harmful pieces into ubiquitinated cytoplasmic perinuclear aggregates as a form of self-defense; (7). Furthermore, mutant htt can go into the nucleus and create nuclear inclusions, which can interfere with transcription and the UPS.

Figure 6

Diagnosis of HD. The initial clinical manifestation of HD is similar to the neurological diseases. Neurological test, definitive genetic examination along with foremost family history is recommended for the diagnosis of HD.