Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at approximately 2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and approximately 30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.
Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein, in this case, ATAXIN-1 (ATXN1). A key question in the field is whether neurotoxicity is mediated by aberrant, novel interactions with the expanded protein or whether its wild-type functions are augmented to a deleterious degree. We examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua. ATXN1 directly binds Capicua and modulates Capicua repressor activity in Drosophila and mammalian cells, and its loss decreases the steady-state level of Capicua. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded ATXN1, substantially reduces the association of mutant ATXN1 with Capicua in vivo. These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions.
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in SCA1. In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein. The mechanism by which this occurs remains enigmatic, however, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in Ataxin1 favors the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology via a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing Ataxin1/Capicua, contributing to SCA1 via a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.Expansion of an unstable translated CAG repeat located in different disease genes so far causes nine dominantly inherited neurodegenerative disorders, the so-called polyglutamine diseases: Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubropallidoluysian atrophy (DRPLA), and six autosomal dominant spinocerebellar ataxias (SCAs) 1 . As would be expected for dominant mutations, polyglutamine expansions confer toxic properties on the host proteins 1-3 ; animal models genetically lacking the polyglutamine-containing proteins do not develop neurodegeneration 4-7 . However, expansion of the polyglutamine tract is necessary but not sufficient to cause pathology: in the case of SCA1, for example, expanded Ataxin1 (ATXN1) does not produce cerebellar degeneration if it lacks the nuclear localization signal 8 or the AXH domain 9 , or if a serine to alanine substitution prevents phosphorylation at residue 776 10 . These and other studies in HHMI Author Manuscript HHMI Author Manuscript HHMI Author ManuscriptSBMA and HD indicate that protein domains outside of the polyglutamine tract play a significant role in the selective neurotoxicity observed in these diseases 11-18 . Moreover, they suggest that there is a relationship between the normal functions of the wild-type proteins and the toxic functions of their expanded counterparts. Given that mouse and fly models overexpressing wild-type ATXN1 develop a mild version of SCA1 19 begs the question of whether the glutamine expansion enhances some interactions to mediate the gain-of-function.To gain a foothold on this question, we sought to characterize protein partners of ATXN1 that interact with it in a manner dependent on two criteria necessary for toxicity: polyglutamine expansion and phosphorylation at serine 776 (S776). We have identified RBM17 (RNA binding motif protein 17) as a protein that meets these criteria. Here we show that ATXN1 forms at least two distinct, large native complex...
Objective There have been no objective assessments to determine whether boys with MECP2 duplication have autism or whether female carriers manifest phenotypes. This study characterizes the clinical and neuropsychiatric phenotypes of affected boys and carrier females. Methods Eight families (9 males and 9 females) with MECP2 duplication participated. A detailed history, physical examination, electroencephalogram, developmental evaluation, Autism Diagnostic Observation Schedule, and Autism Diagnostic Interview – Revised was performed for each boy. Carrier females completed the Symptom Checklist-90-R, Wechsler Abbreviated Scale of Intelligence, Broad Autism Phenotype Questionnaire, and detailed medical and mental health histories. Size and gene content of each duplication were determined by array-CGH. X-chromosome inactivation patterns were analyzed using leukocyte DNA. MECP2 and IRAK1 RNA levels were quantified from lymphoblast cell lines, and Western blots were performed to assess MeCP2 protein levels. Results All of the boys demonstrate mental retardation and autism. Poor expressive language, gaze avoidance, repetitive behaviors, anxiety, and atypical socialization were prevalent. Female carriers have psychiatric symptoms including generalized anxiety, depression, and compulsions that preceded the birth of their children. The majority exhibited features of the broad autism phenotype and had higher nonverbal compared to verbal reasoning skills. Interpretation Autism is a defining feature of the MECP2 duplication syndrome in boys. Females manifest phenotypes despite 100% skewing of X-inactivation and normal MECP2 RNA levels in peripheral blood. Analysis of the duplication size, MECP2 and IRAK1 RNA levels, and MeCP2 protein levels revealed that most of the traits in affected boys are likely due to the genomic region spanning MECP2 and IRAK1. The phenotypes observed in carrier females may be secondary to tissue-specific dosage alterations and require further study.
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