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Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour (1). Mutations in synaptic proteins such as neuroligins (2,3), neurexins (4), GKAPs/SAPAPs (5) and ProSAPs/ Shanks (6-10) were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/ Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion (11,12). Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/[Shank.sup.-/-] mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced JV-methyl-D-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/[Shank.sup.-/-] mutants with ProSAP2/ Shank3α[β.sup.-/-] mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype., Many of the recently identified autism spectrum disorders (ASD) candidate genes code for proteins of excitatory synapses (13-15), suggesting that these disorders may arise from molecular imbalances of synaptic connections. [...]

Recent advances in imaging technology have highlighted that scaffold proteins and receptors are arranged in subsynaptic nanodomains. The synaptic membrane-associated guanylate kinase (MAGUK) scaffold protein membrane protein palmitoylated 2 (MPP2) is a component of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–associated protein complexes and also binds to the synaptic cell adhesion molecule SynCAM 1. Using superresolution imaging, we show that—like SynCAM 1—MPP2 is situated at the periphery of the postsynaptic density (PSD). In order to explore MPP2-associated protein complexes, we used a quantitative comparative proteomics approach and identified multiple γ-aminobutyric acid (GABA)A receptor subunits among novel synaptic MPP2 interactors. In line with a scaffold function for MPP2 in the assembly and/or modulation of intact GABAA receptors, manipulating MPP2 expression had effects on inhibitory synaptic transmission. We further show that GABAA receptors are found together with MPP2 in a subset of dendritic spines and thus highlight MPP2 as a scaffold that serves as an adaptor molecule, linking peripheral synaptic elements critical for inhibitory regulation to central structures at the PSD of glutamatergic synapses. This study shows that the MAGUK scaffold protein MPP2 is located at the periphery of postsynaptic densities in excitatory neurons, where it interacts with GABA-A receptors, thereby serving as a functional adaptor that links excitatory and inhibitory components of synaptic transmission at glutamatergic synapses. [ABSTRACT FROM AUTHOR]

Synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate ( AMPA) receptors are essential mediators of neurotransmission in the central nervous system. Shisa9/cysteine-knot AMPAR modulating protein 44 ( CKAMP44) is a transmembrane protein recently found to be present in AMPA receptor-associated protein complexes. Here, we show that the cytosolic tail of Shisa9/ CKAMP44 interacts with multiple scaffold proteins that are important for regulating synaptic plasticity in central neurons. We focussed on the interaction with the scaffold protein PICK1, which facilitates the formation of a tripartite complex with the protein kinase C ( PKC) and thereby regulates phosphorylation of Shisa9/ CKAMP44 C-terminal residues. This work has implications for our understanding of how PICK1 modulates AMPAR-mediated transmission and plasticity and also highlights a novel function of PKC. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system that leads to progressive loss of upper and lower motor neurons. Most cases are sporadic and of unknown aetiology. In this study, we screened 72 patients with sporadic ALS for the presence of DNA copy number variations, in order to identify novel candidate disease genes. We have used sub-megabase resolution BAC array comparative genomic hybridization to detect genomic imbalances in our ALS patient cohort. Aberrations with potential relevance for disease aetiology were verified by oligo array CGH. In 72 patients with sporadic ALS, we identified a total of six duplications and five deletions that scored above our threshold. Nine of these 11 variations were smaller than 1Mb, and five were observed exclusively in ALS patients. In conclusion, non-polymorphic sub-microscopic duplications and deletions observable by array CGH are frequent in patients with sporadic ALS. Analysis of such aberrations serves as a starting point in deciphering the aetiology of this complex disease, given that affected genes can be considered candidates for influencing disease susceptibility. [ABSTRACT FROM AUTHOR]

Known vertebrate GATA proteins contain two zinc fingers and are required in development, whereas invertebrates express a class of essential proteins containing one GATA‐type zinc finger. We isolated the gene encoding TRPS1, a vertebrate protein with a single GATA‐type zinc finger. TRPS1 is highly conserved between Xenopus and mammals, and the human gene is implicated in dominantly inherited tricho‐rhino‐phalangeal (TRP) syndromes. TRPS1 is a nuclear protein that binds GATA sequences but fails to transactivate a GATA‐dependent reporter. Instead, TRPS1 potently and specifically represses transcriptional activation mediated by other GATA factors. Repression does not occur from competition for DNA binding and depends on a C‐terminal region related to repressive domains found in Ikaros proteins. During mouse development, TRPS1 expression is prominent in sites showing pathology in TRP syndromes, which are thought to result from TRPS1 haploinsufficiency. We show instead that truncating mutations identified in patients encode dominant inhibitors of wild‐type TRPS1 function, suggesting an alternative mechanism for the disease. TRPS1 is the first example of a GATA protein with intrinsic transcriptional repression activity and possibly a negative regulator of GATA‐dependent processes in vertebrate development. [ABSTRACT FROM AUTHOR]

We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder. [ABSTRACT FROM AUTHOR]

The compartmentalization of the plasma membrane (PM) is a fundamental feature of cells. The diffusivity of membrane proteins is significantly lower in biological than in artificial membranes. This is likely due to actin filaments, but assays to prove a direct dependence remain elusive. We recently showed that periodic actin rings in the neuronal axon initial segment (AIS) confine membrane protein motion between them. Still, the local enrichment of ion channels offers an alternative explanation. Here we show, using computational modeling, that in contrast to actin rings, ion channels in the AIS cannot mediate confinement. Furthermore, we show, employing a combinatorial approach of single particle tracking and super-resolution microscopy, that actin rings are close to the PM and that they confine membrane proteins in several neuronal cell types. Finally, we show that actin disruption leads to loss of compartmentalization. Taken together, we here develop a system for the investigation of membrane compartmentalization and show that actin rings compartmentalize the PM. [ABSTRACT FROM AUTHOR]