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Key human anatomy and physiology principles as they relate to rehabilitation engineering
Published in Alex Mihailidis, Roger Smith, Rehabilitation Engineering, 2023
Qussai Obiedat, Bhagwant S. Sindhu, Ying-Chih Wang
Damage to a sensory nerve may lead to inability to detect external stimuli such as touch, pressure, or temperature sensation. If damage occurs to a motor neuron that connects the brain to an effector muscle, an individual may lose the control to move a single or a group of muscles innervated by that nerve. Damage somewhere in the ascending/sensory or descending/motor pathways will interrupt the transmission of the signals. Damage to the cerebellum may lead to a variety of motor control problems including (but not limited to) loss of coordination of motor movement, undershoot or overshoot of intended position with the hand, arm, leg, or eye (dysmetria), inability to perform rapid alternating movements (adiadochokinesia), and staggering, wide-based walking (ataxic gait). Loss of dopamine-secreting cells in the basal ganglia may lead to Parkinson's disease, a slowly progressive neurologic disorder, and is characterized by rigidity or stiffness in movements, slowness of movement, and inability to initiate movement. Accumulating Huntingtin protein in the brain, especially in cells in the basal ganglia, may gradually lead to Huntington's disease, characterized by involuntary movements (chorea), unsteady gait, and slurred speech (Lundy-Ekman 2013).
Applications for Drug Development
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Jessica Kalra, Donald T. Yapp, Murray Webb, Marcel B. Bally
Huntington’s disease is an autosomal dominant disorder in which a CAG trinucleotide repeat is observed in the Huntingtin gene. Late onset symptoms include involuntary choreform movements and cognitive impairment. Histologically, patients have some neuronal loss in the striatum. Animal models of Huntington’s disease (HD) are induced by neurotoxins such as quinolinic acid, ibotenic acid, or 3-nitropropionic acid, which destroy or impair the corticostriatal projection. A rat transgenic HD model has been established using a cDNA carrying 51 CAG trinucleotide repeats under the control of the Huntingtin gene promoter. The transgenic rat exhibits adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and progressive motor dysfunction, as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. Von Horsten et al. have been able to use MRI to image striatal shrinkage and ventricular enlargement in transgenic animals. This group has also used 18F-FDG PET to image brain glucose metabolism and shown a reduction similar to that seen in patients with HD (von Horsten et al. 2003). In 2000, Araujo et al. used micro-PET and [3-(29–18F]fluoroethyl)spiperone to image dopamine receptor binding as well as 18F-FDG to image glucose metabolism in a quinolinic-induced rat model of HD (Araujo et al. 2000).
Huntington’s Disease and Stem Cells
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Karen Ring, Robert O’Brien, Ningzhe Zhang, Lisa M. Ellerby
HTT encodes a large protein called huntingtin (Htt). The protein has 3144 amino acids, and the 3D structure of the full-length protein has not been solved. However, it is predicted to contain huntingtin, EF3, PP2A, and TOR1 (HEAT) repeats that form domains. Molecular modeling predicts that the protein may be involved in mechanical force through movement of the HEAT repeat domains (11). The posttranslational modifications of the protein are extensive and include proteolysis, phosphorylation, sumoylation, acetylation, and lipidation (12–14). Many of the posttranslational modifications have been linked to Htt function or toxicity of the polyQ-expanded form of the protein. Htt is involved in numerous cellular processes including transcriptional regulation, vesicular transport, protein trafficking, synaptic transmission, and inhibition of apoptosis (15). Htt is essential during mammalian development, and mice lacking the protein do not survive (16). Htt is ubiquitously expressed throughout the body but is most abundant in the brain (17). Accordingly, Htt plays important roles in neural cells. Htt directly regulates levels of brain-derived neurotrophic factor (BDNF) and interacts with many other important proteins and transcription factors in the brain such as NeuroD and REST/NRSF complex in order to maintain a neuron-specific transcriptional profile during development and differentiation (5,18–23). However, its exact functions are unknown, making it difficult to determine whether dominant negative properties of mutant Htt (mHtt) lead to loss of function of normal Htt or whether the gain of function in mHtt through interactions with protein-binding partners is responsible for HD pathogenesis.
Exploration of ligand-induced protein conformational alteration, aggregate formation, and its inhibition: A biophysical insight
Published in Preparative Biochemistry and Biotechnology, 2018
Saima Nusrat, Rizwan Hasan Khan
Huntingtin is a 348 kDa protein that is expressed in central nervous system and peripheral tissues, however the disease is manifested in neural tissues.[147] The gene is present on the short arm of chromosome 4 and has a CAG trinucleotide repeat in its first exon. In healthy individuals, the protein has a stretch of 6–35 glutamine residues, however, when the residue number becomes 36 or more, the disease occurs.[142,148] Huntington’s disease is the most common inherited neurodegenerative disorder and is present in 5–10 individuals per 100,000 people around the world.