The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation

Macromolecular transport in synapse to nucleus communication

“…This transport mechanism is strikingly analogous to that previously described for protected transport of phosphorylated ERK from injured peripheral axons to the soma in association with proteolytic fragments of the intermediate filament vimentin [48,49]. Moreover, a recent study showing that proline-rich synapse-associated protein 2 (ProSAP2)/SH3 and multiple ankyrin repeat domains 3 (Shank3) translocates to the nucleus in an activity-dependent manner [50] provides further support for the idea that mobile hubs coordinate larger signaling complexes in synapse to nucleus transport. ProSAP2/Shank3 is a synaptic scaffolding protein that directly interacts with proteins such as Lapser1 [51] and Abelson interacting protein 1 (Abi-1) [52], which have also been shown to transit to the nucleus from synaptic sites and have roles in regulation of gene transcription.…”

Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3

“…At the moment it still needs to be elucidated how SHANK3 can mediate a regulatory role on transcriptional events, however, the ability of the protein to localize to the nucleus4862 and data presented here might indicate that SHANK3 can not only function as a scaffolding molecule but also as a component of transcriptional complexes. In turn, this would imply that mutations of the SHANK3 gene can directly cause alterations of transcriptional activity in defined tissues and cell types.…”

“…4c). Overexpression of a mutated SHANK3 protein (GFP-SHANK3 R1119X) that has been associated with schizophrenia and that is permanently localized in the nucleus48 does not result in a significant increase in ZIP2 and ZIP4 mRNA and protein levels. However, a clear trend towards an increase is visible (Supplementary Fig.…”

Sensitivity to isoflurane anesthesia increases in autism spectrum disorder Shank3 +/∆c mutant mouse model

“…23,69–72 PSD95, a scaffolding protein in the Shank3 signaling pathway, is an important molecule in NMDA receptor-mediated signal transmission. 73,74 Knocking down PSD95 75 and disrupting NMDAR-PSD95 interactions 35 in spinal cord can reduce isoflurane MAC.…”