SHANK1

SHANK1

A gene on chromosome 19q13.3 that encodes a member of the Shank gene family, which are multidomain scaffold proteins of the postsynaptic density (PSD) involved in synapse formation and dendritic spine maturation. The PSD connects neurotransmitter receptors, ion channels and other membrane proteins to the actin cytoskeleton and G protein-coupled signalling pathways.
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It was shown that the overexpression of zinc-sensitive ProSAP1/Shank2 or ProSAP2/Shank3 increases synapse density, whereas depletion of synaptic zinc along with the knockdown of zinc-insensitive Shank1 causes the rapid disintegration of PSD and the loss of several postsynaptic molecules including NMDARs [137].
Deregulation of ProSAP/Shank has been reported in AD: in patients brains and in transgenic mice models, the accumulation of A[beta] oligomers is accompanied by reduction of synaptic scaffold protein levels, such as Shank1 and ProSAP2/Shank3 [115], and disruption of the Homer1b and Shank1 scaffolds [116].
The members of the Shank/ ProSAP family, Shank1, Shank2, and Shank3, are multidomain scaffold proteins located at the PSD of glutamatergic synapses that interact with a large variety of membrane and cytoplasmic proteins.
Human genetic studies have strongly linked Shank genes, including Shank1, Shank2, and Shank3, with Phelan-McDermid syndrome (PMS), ASD, AD, and SCZ associated with ID [250,260,263].
Sala et al., "Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1," The Journal of Neuroscience, vol.
Crawley, "Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior," PLoS ONE, vol.
Wolwer et al., "A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis," European Archives of Psychiatry and Clinical Neuroscience, vol.
The Shank family of scaffolding proteins has three known members (Shank1, 2, 3) and binds to the GKAP (guanylate kinase-associated protein) scaffolding protein via Shank's PDZ domain.