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CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.
Journal article

CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.

  • Bidinosti M Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Botta P Friedrich Miescher Institute, Basel, Switzerland.
  • Krüttner S Friedrich Miescher Institute, Basel, Switzerland.
  • Proenca CC Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Stoehr N Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Bernhard M Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Fruh I Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Mueller M Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Bonenfant D Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Voshol H Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Carbone W Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Neal SJ Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA.
  • McTighe SM Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA.
  • Roma G Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Dolmetsch RE Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA.
  • Porter JA Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Caroni P Friedrich Miescher Institute, Basel, Switzerland.
  • Bouwmeester T Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Lüthi A Friedrich Miescher Institute, Basel, Switzerland.
  • Galimberti I Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ivan.galimberti@novartis.com.
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  • 2016-02-06
Published in:
  • Science (New York, N.Y.). - 2016
Amino Acid Sequence
Animals
Autism Spectrum Disorder
Chromosome Deletion
Chromosome Disorders
Chromosomes, Human, Pair 22
Disease Models, Animal
Down-Regulation
Gene Knockdown Techniques
Humans
Insulin-Like Growth Factor I
Mechanistic Target of Rapamycin Complex 1
Mice
Molecular Sequence Data
Multiprotein Complexes
Nerve Tissue Proteins
Neurons
Phosphorylation
Protein Phosphatase 2
Protein-Serine-Threonine Kinases
Protein-Tyrosine Kinases
Proteomics
Proto-Oncogene Proteins c-akt
Rats
Signal Transduction
TOR Serine-Threonine Kinases
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/232388
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