Huntington’s Disease
Huntington’s disease (HD) is a progressive neurological disorder, where areas of the brain are damaged or changed that causes various symptoms, such as uncontrolled movements, emotional problems, and loss of thinking ability (cognitive deficits) (Rubinsztein, 2003; Finkbeiner, 2011; Zuccato, et al., 2010). HD is an autosomal dominant disorder caused by a genomic expansion mutation to the Huntingtin (HTT) gene on chromosome 4. The HTT gene possesses a repeating trinucleotide sequence of cytosine–adenine–guanine (CAG) coding for a polyglutamine (PolyQ) in the N-terminal region of the Huntington (Htt) protein. The PolyQ is usually present in low amounts with an average of 15 – 20 repeats (Hakim-Eshed, et al., 2020). When the HTT gene is mutated and the number of repeats exceeds ~40, the mutant Huntington (mHtt) protein will misfold, aggregate and become toxic, causing neurodegeneration or neural cell death (Rubinsztein, 2003; Finkbeiner, 2011). The striatum (Caudate nucleus and Putamen) is the part of the brain that is mostly affected by HD.
In HD, the misfolding and aggregation of mHtt proteins form inclusions in striatal neurons, which is suggested to be the cause of neurodegeneration and cell death. The length of the CAG repeats plays a critical role in determining the mHtt aggregation process (Zuccato, et al., 2010). An important intracellular pathway for reducing the levels of misfolded or aggregated proteins is the normal cellular protein cleaning process: Ubiquitin-Proteasome System (UPS), which is found to be dysfunctional and compromised in mHtt clearance in HD (Zuccato, et al., 2010; Hipp, et al., 2012). Therefore, degrading mutant huntingtin protein (mHtt) or inhibiting mHtt aggregate formation is considered to be the therapeutic approaches. Currently, there is no cure for HD. Available treatment is only to ameliorate and pacify the symptoms (Rubinsztein, 2003).
References:
1. Finkbeiner. (2011). Huntington’s Disease. Cold Spring Harb Perspect Biol 2011;3:a007476
2. Hakim-Eshed et al., (2020). Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects. PNAS. 117 (31), 18661-18669.
3. Hipp et al. (2012). Indirect inhibition of 26S proteasome activity in a cellular model of Huntington’s disease. J. Cell Biol. 196 (5) 573–587 www.jcb.org/cgi/doi/10.1083/jcb.201110093
4. Rubinsztein. (2003). The molecular pathology of Huntington’s Disease (HD). Curr. Med. Chem.-Immun., Endoc, & Metab. Agents, 3 (4), 329-340.
5. Zuccato, C. ∙ Cattaneo, E. (2007). Role of brain-derived neurotrophic factor in Huntington’s disease. Prog. Neurobiol. 81:294-330.