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A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders
Author(s) -
Grabrucker Andreas M.
Publication year - 2014
Publication title -
developmental neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.716
H-Index - 129
eISSN - 1932-846X
pISSN - 1932-8451
DOI - 10.1002/dneu.22089
Subject(s) - neuroscience , scaffold protein , synaptic plasticity , biology , postsynaptic density , postsynaptic potential , glutamatergic , metaplasticity , dendritic spine , synapse , neurotransmission , signal transduction , microbiology and biotechnology , excitatory postsynaptic potential , glutamate receptor , inhibitory postsynaptic potential , receptor , genetics , hippocampal formation
The establishment and maintenance of synaptic contacts as well as synaptic plasticity are crucial factors for normal brain function. The functional properties of a synapse are largely dependent on the molecular setup of synaptic proteins. Multidomain proteins of the ProSAP/Shank family act as major organizing scaffolding elements of the postsynaptic density (PSD). Interestingly, ProSAP/Shank proteins at glutamatergic synapses have been linked to a variety of Autism Spectrum Disorders (ASDs) including Phelan McDermid Syndrome, and deregulation of ProSAP/Shank has been reported in Alzheimer's disease. Although the precise molecular mechanism of the dysfunction of these proteins remains unclear, an emerging model is that mutations or deletions impair neuronal circuitry by disrupting the formation, plasticity and maturation of glutamatergic synapses. Several PSD proteins associated with ASDs are part of a complex centered around ProSAP/Shank proteins and many ProSAP/Shank interaction partners play a role in signaling within dendritic spines. Interfering with any one of the members of this signaling complex might change the output and drive the system towards synaptic dysfunction. Based on recent data, it is possible that the concerted action of ProSAP/Shank and Zn 2+ is essential for the structural integrity of the PSD. This interplay might regulate postsynaptic receptor composition, but also transsynaptic signaling. It might be possible that environmental factors like nutritional Zn 2+ status or metal ion homeostasis in general intersect with this distinct pathway centered around ProSAP/Shank proteins and the deregulation of any of these two factors may lead to ASDs. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 136–146, 2014