HTT and Associated Diseases
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Backgrounds of Huntingtin (HTT)
Huntingtin (HTT) is a common scaffold protein because its mutation causes a severe and incurable hereditary neurological disorder, Huntington's disease (HD). Human HTT is a large protein of 3144 amino acids. Htt is associated with a variety of organelles, including the nucleus, endoplasmic reticulum, Golgi complex, synaptic vesicles, and mitochondria. It is widely expressed in the brain and body and distributed in various subcellular regions. Also, Htt is expressed in the brain throughout development and plays a vital role in neuronal survival and stability. In the brain, Htt is primarily localized in the cytoplasm of neurons. HTT contains both nuclear export and nuclear localization signals, so the protein shuttles between the nucleus and cytoplasm via active transport. Normal Htt is predominantly localized in the cytoplasm, whereas mutant Htt with its expanded polyQ domain accumulates in the nucleus.
Fig.1 Production of huntingtin protein (HTT) and targeted molecular therapies in development to reduce its expression. (Wild, 2017)
Functions of HTT
- HTT is involved in many cellular functions essential for central nervous system physiology, such as cell division, transcriptional regulation, and intracellular trafficking. HTT is involved in the development of the central nervous system, including neural tube formation and neuroblast migration. It is also involved in axonal transport, synaptic function, and cell survival.
- HTT can act as a tumor suppressor and regulate the apoptosis of tumor cells.
- HTT has also been implicated in the regulation of components of adherence junctions.
- The role of HTT in cell adhesion may play a key role during embryonic neurogenesis, as neuronal adhesion and polarity are essential for the establishment of functional networks.
Mutations in the Htt Gene and Associated Diseases
Mutant Htt has been found to bind to several transcription factors, including TATA-binding proteins, Sp1, and the nuclear scaffold protein NAKAP. Mutant Htt interactions may interfere with gene expression, activity, and transcriptional regulation in HD neurons. Mutated Htt interacts with a large number of brain proteins, and the extent of this interaction depends on the number of expanded polyglutamine repeats. This interaction of mutant proteins ultimately leads to the gain of function of mutant Htt in HD progression. HD is an inherited autosomal dominant disorder thought to be caused by toxic gains of function; thus, a reduction in mutant HTT production should alleviate its pathogenesis. In the context of HD, mutant HTT proteins form insoluble nuclear aggregates that are thought to play a key role in neuronal cell death. Mutant Htt also acts in the cytoplasm, affecting cellular function. Several studies reported that mutant Htt in association with mitochondria and microtubules impairs the axonal transport of mitochondria to nerve terminals.
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Reference
- Wild, E.J.; Tabrizi, S.J. Therapies targeting DNA and RNA in Huntington's disease. The Lancet Neurology. 2017, 16(10): 837-847.
