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

作者：Grabrucker Stefanie; Proepper Christian; Mangus Katharina; Eckert Matti; Chhabra Resham; Schmeisser Michael J; Boeckers Tobias M; Grabrucker Andreas M^*

来源：Experimental Neurology, 2014, 253: 126-137.

DOI：10.1016/j.expneurol.2013.12.015

• SCZ
• Synapse
• Shank3
• hnRNP
• Autism
• PSD
• Nuclear shuttling
• LRRTM1
• Synaptotagmin 1

Recently, mutations in ProSAP2/Shank3 have been discovered as one of the genetic factors for schizophrenia (SCZ). Here, we show that the postsynaptic density protein ProSAP2/Shank3 undergoes activity dependent synapse-to-nucleus shuttling in hippocampal neurons. Our study shows that the de novo mutation (R1117X) in ProSAP2/Shank3 that was identified in a patient with SCZ leads to an accumulation of mutated ProSAP2/Shank3 within the nucleus independent of synaptic activity. Furthermore, we identified novel nuclear ProSAP2/Shank3 interaction partners. Nuclear localization of mutated ProSAP2/Shank3 alters transcription of several genes, among them already identified genetic risk factors for SCZ such as Synaptotagmin 1 and LRRTM1. Comparing the SCZ mutation of ProSAP2/Shank3 to the knockdown of ProSAP2/Shank3 we found some shared features such as reduced synaptic density in neuronal cultures. However, hippocampal neurons expressing the ProSAP2/Shank3 SCZ mutation furthermore show altered E/I ratio and reduced dendritic branching. Thus, we conclude that the uncoupling of ProSAP2/Shank3 nuclear shuttling from synaptic activity may represent a molecular mechanism that contributes to the pathology of SCZ in patients with mutations in ProSAP2/Shank3.

• 出版日期2014-3