HD Mechanism of Action (MoA) Studies
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by striatal pathology, and its most prominent symptoms include uncontrolled chorea-like movements, mental disorders, progressive dementia, and typical cognitive and emotional deficits. The pathology of HD has been studied for many years, and a better understanding of its MoA greatly contributes to clinical guidance, drug development, and symptom relief or even avoidance of the disease. No matter what stage of your HD MoA study program, if you're validating your target, or ready to advance your lead candidate, Creative Biolabs offers relevant one-stop HD MoA study services to enhance your program efficacy.
Pathology of HD
One of the biggest features of HD is that it is inherited through autosomal dominant inheritance, so genetic testing can intuitively determine the risk of the disease. In 1993, the International Huntington's Disease Cooperative Research Group named the IT35 gene, which is located on the upper part of chromosome 4 and has a unique DNA glutamine trinucleotide repeat feature, as the huntingtin gene (HTT). Huntingtin, a metabolite of the HTT gene, is distributed throughout the body, but its function under normal conditions has not been fully elucidated.
In recent years, studies have shown that HTT protein can interact with more than 200 kinds of partners in cells and participate in various cellular activities, such as transcriptional regulation, nucleocytoplasmic shuttling, synaptic function and apoptosis. Abnormal HTT protein, encoded by the mutated HTT gene (mHTT gene), is often detected in HD patients. The CAG codon in this gene edits the polyglutamine chain (polyQ), and when the number exceeds 40, it produces an elongated polyQ stretch at the N-terminus of the HTT protein. Abnormal HTT protein structures tend to adhere to each other and aggregate in the nuclear, known as inclusions of neuronal nuclear (INN). The presence of INNs was associated with behavioral deficits, and their numbers also determined the severity of HD symptoms.
Fig 1. Potential toxic species in HD and mechanisms for HTT lowering. (Sarah, et al., 2019)
Much of the intracellular signaling cascade surrounding excitotoxicity in HD has been pieced together in recent years, with two key players, NMDA and PSDP-95. HTT proteins with extended polyQ interfere with their interaction with the respective receptors, causing both receptors to become hypersensitive, induce excitotoxicity, and neuronal cell death, which in turn leads to basal ganglia and neuronal loss, ultimately leading to HD.
Our Related Services
For your research project, we provide a range of HD MoA study services including Huntingtin-Lowering therapies study and many others. No matter you want to start with animal models or to analyze directly at the gene and protein level, our professional and well-trained specialists can provide you with suitable services, so please contact us and discuss your needs, for us to deliver an appealing proposal.
Reference
- Sarah, J.T.; et al. Huntingtin lowering strategies for disease modification in Huntington's Disease. Neuron. 2019, 101: 801-819.
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