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• W2089759630 abstract "Angelman syndrome (AS) is a severe neurological disorder characterized by seizures, ataxia, and cognitive dysfunction. AS occurs in ∼1 of every 15,000 births and appears to arise from the functional loss of a maternally expressed imprinted gene or genes. The majority of cases are attributable to a chromosomal deletion on the maternally inherited chromosome 15 (see figure). Loss of the functional maternal allele in AS also occurs by paternal uniparental disomy (UPD), in which two copies of chromosome 15 are inherited from the father, by defects in the imprinting process (7Nicholls R.D. Saitoh S. Horsthemke B. Trends Genet. 1998; 14: 194-200Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar), and it recently has been shown to arise from gene mutation of the maternally inherited allele of UBE3A, an E3 ubiquitin ligase (see figure; 5Malzac P. Webber H. Moncla A. Graham J.M. Kukolich M. Williams C. Pagon R.A. Ramsdell L.A. Kishino T. Wagstaff J. Am. J. Hum. Genet. 1998; 62: 1353-1360Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). The paper by 3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar in this issue of Neuron confirms the importance of UBE3A in AS, by demonstrating in a mouse model that a mutation in the maternal allele of Ube3a is sufficient for an AS-like phenotype. This result raises the interesting question of why a mutation in a gene involved in a general cellular process such as ubiquitin-mediated protein degradation should have such specific neurological consequences; these mutant mice may in fact be just the tools to address this question. Many aspects of cellular function require regulatory protein turnover, and the process of ubiquitin-mediated protein degradation by the 26S proteasome is a key component of this regulation (2Hochstrasser M. Curr. Opin. Cell Biol. 1995; 7: 215-223Crossref PubMed Scopus (763) Google Scholar, 4Johnson P.R. Hochstrasser M. Trends Cell Biol. 1997; 7: 408-413Abstract Full Text PDF PubMed Scopus (68) Google Scholar). The ubiquitin ligases are thought to present ubiquitinated substrate proteins bound for degradation to the proteasome complex. The cellular function of UBE3A is unknown, despite its initial identification as E6-associated protein (E6-AP), a cellular protein required for the degradation of p53. p53 has major roles in control of the cell cycle and apoptosis and turns over rapidly in normal cells. With the generation of mice deficient in Ube3a, 3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar now provide critical results and reagents for the definition of the molecular role of UBE3A, and perhaps p53, in neuronal function, particularly in the cerebellum and hippocampus. Human genetics of AS predicts that UBE3A is imprinted and only the maternal allele is expressed (7Nicholls R.D. Saitoh S. Horsthemke B. Trends Genet. 1998; 14: 194-200Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). Indeed, in the mice, paternal transmission (p−/m+) of the mutant Ube3a allele is phenotypically silent, whereas maternal deficiency (m−/p+) represents a genetic model of AS and generates mice that, while viable and fertile, have a characteristic phenotype consistent with AS. This includes fine motor skill and coordination deficits, abnormal electrencephalogram (EEG) recordings and inducible seizures, an impairment of hippocampal long-term synaptic potentiation (LTP), and abnormally high cytoplasmic p53 levels in postmitotic neurons (3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar). The LTP results correlate with a defect in context-dependent learning in these mice, which is suggested to be analogous to the severe cognitive impairment in AS (Jiang et al., 1988). Interestingly, the defects in Ube3a (m−/p+) mice occur despite apparently normal neuroanatomy, even in cerebellar Purkinje cells and hippocampal neurons, the cell types showing brain-specific imprinting of Ube3a (3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar). Is AS caused solely by UBE3A deficiency? From human (11Williams C.A. Zori R.T. Hendrickson J. Stalker H. Marum T. Whidden E. Driscoll D.J. Curr. Prob. Pediat. 1995; 25: 216-231PubMed Google Scholar, 5Malzac P. Webber H. Moncla A. Graham J.M. Kukolich M. Williams C. Pagon R.A. Ramsdell L.A. Kishino T. Wagstaff J. Am. J. Hum. Genet. 1998; 62: 1353-1360Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) and mouse (3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar) studies, it is clear that mutations in this gene lead to most of the typical neurobehavioral features of AS, including ataxia, seizures, and severe mental retardation, albeit to a lesser degree in the mouse then in humans. However, several human studies suggest more severe and frequent seizures, ataxia, and lower cognitive function in AS patients with maternal deletions than in AS patients with UPD, imprinting defects, or UBE3A mutations (11Williams C.A. Zori R.T. Hendrickson J. Stalker H. Marum T. Whidden E. Driscoll D.J. Curr. Prob. Pediat. 1995; 25: 216-231PubMed Google Scholar, 6Minassian B.A. DeLorey T.M. Olsen R.W. Philippart M. Bronstein Y. Zhang Q. Guerrini R. Van Ness P. Livet M.O. Delgado-Escueta A. Ann. Neurol. 1998; 43: 485-493Crossref PubMed Scopus (157) Google Scholar). Consequently, it has been suggested that nonimprinted genes deleted in AS may contribute to the phenotype, and that the GABAA receptor β3 subunit (GABRB3) gene (see figure), in particular, may contribute to the seizure phenotype in AS (1DeLorey T.M. Handforth A. Anagnostaras S.G. Homanics G.E. Minassian B.A. Asatourian A. Fanselow M.S. Delgado-Escueta A. Ellison G.D. Olsen R.W. J. Neurosci. 1998; in pressGoogle Scholar, 6Minassian B.A. DeLorey T.M. Olsen R.W. Philippart M. Bronstein Y. Zhang Q. Guerrini R. Van Ness P. Livet M.O. Delgado-Escueta A. Ann. Neurol. 1998; 43: 485-493Crossref PubMed Scopus (157) Google Scholar). Since the same chromosomal region is deleted on the paternal chromosome in Prader-Willi syndrome, and these patients do not have seizures or other AS features (7Nicholls R.D. Saitoh S. Horsthemke B. Trends Genet. 1998; 14: 194-200Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar), simple deletion of one GABRB3 allele is unlikely to explain seizures in AS. However, homozygous null Gabrb3 mice that survive cleft palate in the newborn period show phenotypic similarities to AS (1DeLorey T.M. Handforth A. Anagnostaras S.G. Homanics G.E. Minassian B.A. Asatourian A. Fanselow M.S. Delgado-Escueta A. Ellison G.D. Olsen R.W. J. Neurosci. 1998; in pressGoogle Scholar), including EEG abnormalities, seizures, learning and memory deficits, hyperactivity, and a disturbed rest–activity cycle (the latter not yet tested in Ube3a-deficient mice). Therefore, if there is a role for anomalous GABAA neurotransmission in AS, this would have to involve a threshold effect with a concomitant reduction in GABRB3 gene expression accompanying loss of maternally inherited UBE3A function. Studies of Ube3a (m−/p+) (3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar) and hemizygous (−/+) Gabrb3 (1DeLorey T.M. Handforth A. Anagnostaras S.G. Homanics G.E. Minassian B.A. Asatourian A. Fanselow M.S. Delgado-Escueta A. Ellison G.D. Olsen R.W. J. Neurosci. 1998; in pressGoogle Scholar) mutant mice, as well as comparison to AS mouse models with large chromosomal deletions, may allow determination of whether severe seizures or other phenotypic features in AS require Gabrb3 or any other Ube3a-linked gene. UBE3A’s involvement in protein degradation raises a number of questions. For instance, although UBE3A clearly targets specific ubiquinated ligands to the proteasome protein degradation pathway, might it also play a role in ubiquitin-like protein trafficking pathways (4Johnson P.R. Hochstrasser M. Trends Cell Biol. 1997; 7: 408-413Abstract Full Text PDF PubMed Scopus (68) Google Scholar)? Does stabilization of cytoplasmic p53 play a role in the cellular basis of AS? Although p53 is required for some but not all neuronal apoptosis pathways (8Sadoul R. Quiquerez A.-L. Martinou I. Fernandez P.A. Martinou J.-C. J. Neurosci. Res. 1996; 43: 594-601Crossref PubMed Scopus (34) Google Scholar), it is not clear what function, if any, p53 may have in postmitotic neurons. It does appear to play a role in seizure-induced brain injury, and loss of p53 protects neurons from excitotoxin treatment (9Sakhi S. Bruce A. Sun N. Tocco G. Baudry M. Schreiber S.S. Proc. Natl. Acad. Sci. USA. 1994; 91: 7525-7529Crossref PubMed Scopus (245) Google Scholar, 12Xiang H. Hochman D.W. Saya H. Fujiwara T. Schwartzkroin P.A. Morrison R.S. J. Neurosci. 1996; 16: 6753-6765Crossref PubMed Google Scholar). Therefore, analysis of seizure susceptibility and neuronal phenotype of mice deficient in both Ube3a (3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar) and p53 function (10Williams B.O. Remington L. Albert D.M. Mukai S. Bronson R.T. Jacks T. Nat. Genet. 1994; 7: 480-484Crossref PubMed Scopus (337) Google Scholar) may be particularly instructive as to the role of p53 in the nervous system and as to whether overproduction of the p53 protein plays a role in the neuropathogenesis of AS. In conclusion, the development of specific mouse models of AS, particularly the Ube3a (m−/p+) knockout mutation (3Jiang Y.-H. Armstrong D. Albrecht U. Atkins C.M. Noebels J.L. Eichele G. Sweatt J.D. Beaudet A.L. Neuron. 1998; 21 (this issue): 799-811Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar), will be critical for determining the biochemical and physiological pathways within the cerebellum and hippocampus for protein turnover mediated by the Ube3a E3 ubiquitin ligase. Ultimately, the hope is that AS animal models will allow investigation of potential therapeutic approaches toward amelioration of neurological and behavioral deficits in Angelman syndrome." @default.
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• W2089759630 title "Strange Bedfellows? Protein Degradation and Neurological Dysfunction" @default.
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