Abstract
Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.
Highlights
Autism spectrum disorder (ASD) and schizophrenia are disorders with some intersecting clinical characteristics such as their shared impairment of social cognition [1,2,3,4]
The resultant dysbindin network contained 119 proteins. Six of these dysbindin interactome components were common to gene products whose mRNA expression is sensitive to Mecp2 content as previously determined by microarrays (Fig. 1) [29]
Pallidin (Pldn), peroxiredoxin 1 (Prdx1), COG7, pleiotrophin (PTN), ADP-ribosylation factor interacting protein 2 (ARFIP2), huntingtin-associated protein 1 (HAP1), and discoidin domain receptor tyrosine kinase 1 (DDR1) mRNAs are increased in MECP2 over-expressing mouse neurons (Fig. 1A, Mecp2Tg/y) and decreased in Mecp2-null mouse neurons (Fig. 1B, Mecp22/y)
Summary
Autism spectrum disorder (ASD) and schizophrenia are disorders with some intersecting clinical characteristics such as their shared impairment of social cognition [1,2,3,4] Phenotypic similarities between these disorders suggest common molecular roots [5]. An increasing number of copy number variations that span multiple genes associate with both schizophrenia and ASD [11,12] This supportive genetic evidence extends to monogenic defects such as those in GPHN [13], ANK3 [14], NRXN1 or MECP2. Mutations to Mecp affect the neuronal expression of 12–15% of the mouse genome [28,29], suggesting that some of these MeCP2-regulated transcripts could encode unrecognized synaptic proteins associated with schizophrenia pathogenesis. We focus on a MeCP2-dependent mechanism that regulates the expression of subunits of the biogenesis of lysosome related organelles complex 1 (BLOC-1), a synaptic complex that contains the schizophrenia-associated protein, dysbindin
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
