title: The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.
abstract: 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.
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany; Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Grabrucker
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Proepper
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mangus
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Matti
authors.initials: M
authors.lastname: Eckert
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Resham
authors.initials: R
authors.lastname: Chhabra
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schmeisser
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany; Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany. Electronic address: andreas.grabrucker@uni-ulm.de.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Grabrucker
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D013997:Time Factors
chemical_list: C561490:LRRTM1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C492357:SHANK3 protein, human; D001120:Arginine
keywords: Autism; LRRTM1; Nuclear shuttling; PSD; SCZ; Shank3; Synapse; Synaptotagmin 1; hnRNP