GLOBAL & TARGETED PROFILING OF PROTEIN, PHOSPHO AND O-GLCNAC TO UNDERSTAND SYNAP

University Of California, San Francisco, San Francisco CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cognitive brain functions, including learning and memory, are based on the properties of networks of neurons, and their ability to modify their output as a function of prior experience. The network properties in turn are the result of the interaction of cellular components and their underlying molecular machinery. Synapses, the connection points between neurons, exhibit both short-term and long-term use-dependent plasticity and therefore play a central role in the neuronal networks. Mammalian brain synapses contain more than 1000 unique proteins, which participate in multiple interconnected signaling pathways following the stimulation of postsynaptic neurotransmitter receptors. Importantly, reversible posttranslational modifications (PTMs) greatly extend the genetically encoded complexity of synapses. Autism is arguably the most common cognitive neurodevelopmental disorder. The underlying molecular cause for autism spectrum disorders (ASDs) is still elusive. However, where genetic or biochemical alterations were identified and linked to smaller ASD subgroups, they point towards synaptic dysfunction as a common theme. In summary, in ASDs it is likely that synaptic signaling pathways do not respond adequately to synaptic input, leading, for example, to impaired short-term or long-term synaptic plasticity, or impaired synaptic stability. Gene dose effects on synaptic signaling imply that the homeostatic levels of key synaptic proteins must be well controlled in order to have fully functional synapses. Here we are proposing to conduct an in-depth proteomic system-type pilot investigation into synaptic proteins from two sets of autism-related samples: frozen post-mortem brains of individuals affected by autism;and synapses isolated from a mouse model of Angelman syndrome.