Following endocytosis, ubiquitinated receptors are sorted for lysosomal degradation, thereby preventing their recycling to the plasma membrane. Ubiquitination is a key process in the regulation of synapse formation and function. Since, its physiological substrate is thought to be mono- or oligoubiquitinated, rather than representing a polyubiquitinated protein destined for degradation at the proteasome, Usp14 may have several functions in ubiquitin-signaling pathways. Although the proteasome is likely to be involved in the neurological dysfunctions, Usp14 is unable to process polyubiquitin chains. Ax J mice display an exclusive downregulation of the full-length isoform, thereby representing a specific knockdown of the proteasome binding form of Usp14. Accordingly, binding of Usp14 to the proteasome is thought to be necessary for efficient hydrolyse activity of Usp14. The full-length isoform contains an addition of 33 amino acids, required for proteasome binding. Upon alternative splicing of exon 4, two isoforms of Usp14 are generated. Usp14 catalyzes the hydrolysis of isopeptide bonds in ubiquitin-protein conjugates. Due to insertion of an intracisternal A-particle into intron 5, expression levels of full-length Usp14 in brains of ax J mice are reduced to about 5%. The mutated gene encodes the deubiquitinating enzyme (DUB) Usp14, a member of the ubiquitin-specific protease family. The spontaneous ax J mutation affects the locomotory system, causing an ataxic phenotype in mice. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.Ī number of heterogeneous hereditary and non-hereditary disorders lead to ataxia characterized by coordination failures. Furthermore, by NIH Neuroscience Blueprint Core Grant NS57098 to the University of Alabama at Birmingham and NIH/NINDS grant NS047533 to SMW. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: Supported by the University of Hamburg, Deutsche Forschungsgemeinschaft (DFG 556/1-3 DFG FG885-556/4-1), and the Chica and Heinz-Schaller Society to MK. Received: DecemAccepted: AugPublished: September 4, 2009Ĭopyright: © 2009 Lappe-Siefke et al. Frankel, The Jackson Laboratory, United States of America (2009) The Ataxia ( ax J) Mutation Causes Abnormal GABA A Receptor Turnover in Mice.
Citation: Lappe-Siefke C, Loebrich S, Hevers W, Waidmann OB, Schweizer M, Fehr S, et al.
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