title: CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.
abstract: SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56β, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Michael
authors: M
authors: Bidinosti
authors: Friedrich Miescher Institute, Basel, Switzerland.
authors: Paolo
authors: P
authors: Botta
authors: Friedrich Miescher Institute, Basel, Switzerland.
authors: Sebastian
authors: S
authors: Krüttner
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Catia C
authors: CC
authors: Proenca
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Natacha
authors: N
authors: Stoehr
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Mario
authors: M
authors: Bernhard
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Isabelle
authors: I
authors: Fruh
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Matthias
authors: M
authors: Mueller
authors: Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Debora
authors: D
authors: Bonenfant
authors: Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Hans
authors: H
authors: Voshol
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Walter
authors: W
authors: Carbone
authors: Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA.
authors: Sarah J
authors: SJ
authors: Neal
authors: Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA.
authors: Stephanie M
authors: SM
authors: McTighe
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Guglielmo
authors: G
authors: Roma
authors: Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA.
authors: Ricardo E
authors: RE
authors: Dolmetsch
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Jeffrey A
authors: JA
authors: Porter
authors: Friedrich Miescher Institute, Basel, Switzerland.
authors: Pico
authors: P
authors: Caroni
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Tewis
authors: T
authors: Bouwmeester
authors: Friedrich Miescher Institute, Basel, Switzerland.
authors: Andreas
authors: A
authors: Lüthi
authors: Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ivan.galimberti@novartis.com.
authors: Ivan
authors: I
authors: Galimberti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000201:enzymology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C492356:Shank3 protein, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2