Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
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Early-onset torsion dystonia is a hyperkinetic movement disorder caused by a deletion of one glutamic acid residue in torsinA, a novel member of the AAA-family of ATPases. No mutation has been found so far in the closely related torsinB protein. Little is known about the molecular basis of the disease, and the cellular functions of torsin proteins remain to be investigated. We generated polyclonal anti-peptide antibodies directed against human torsinA and torsinB proteins. In Western blot analysis of mouse brain homogenates, the antibodies specifically recognized 33 kDa endogenous torsinA and 52 kDa endogenous torsinB. Absorption controls showed that labeling was blocked by cognate peptide used for immunization. Immunolocalization studies revealed that torsinA and torsinB were widely expressed throughout the mouse central nervous system. Both proteins were detected in the majority of neurons in nearly all regions. The proteins displayed cytoplasmic distribution, although in some types of neurons localization was perinuclear. Strong labeling of neuronal processes and fibers was detected for both proteins. TorsinA and torsinB have similar CNS distribution, although some differences were observed. Widespread expression suggests that these proteins may play an essential role in normal neuronal functions. The localization of torsinA and torsinB immunoreactivity in neuronal processes points to a potential role for torsin proteins in synaptic functioning.
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PMID:Immunocytochemical characterization of torsin proteins in mouse brain. 1173 Jun 96

Most cases of early-onset torsion dystonia are caused by deletion of GAG in the coding region of the DYT1 gene encoding torsinA. This autosomal dominant neurologic disorder is characterized by abnormal movements, believed to originate from neuronal dysfunction in the basal ganglia of the human brain. The torsins (torsinA and torsinB) are members of the "ATPases associated with a variety of cellular activities" (AAA(+)) superfamily of proteins that mediate chaperone and other functions involved in conformational modeling of proteins, protection from stress, and targeting of proteins to cellular organelles. In this study, the intracellular localization and levels of endogenous torsin were evaluated in rat pheochromocytoma PC12 cells following differentiation and stress. TorsinA, apparent MW 37 kDa, cofractionates with markers for the microsomal/endoplasmic reticulum (ER) compartment and appears to reside primarily within the ER lumen based on protease resistance. TorsinA immunoreactivity colocalizes with the lumenal ER protein protein disulfide isomerase (PDI) and extends throughout neurites. Levels of torsinA did not increase notably in response to nerve growth factor-induced differentiation. None of the stress conditions tested, including heat shock and the unfolded protein response, affected torsinA, except for oxidative stress, which resulted in an increase in the apparent MW of torsinA and redistribution to protrusions from the cell surface. These findings are consistent with a relatively rapid covalent modification of torsinA in response to oxidative stress causing a change in state. Mutant torsinA may interfere with and/or compromise ER functions, especially in dopaminergic neurons, which have high levels of torsinA and are intrinsically vulnerable to oxidative stress.
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PMID:TorsinA in PC12 cells: localization in the endoplasmic reticulum and response to stress. 1267 90