CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency

Michael Bidinosti; Paolo Botta; Sebastian Krüttner; Catia C Proenca; Natacha Stoehr; Mario Bernhard; Isabelle Fruh; Matthias Mueller; Debora Bonenfant; Hans Voshol; Walter Carbone; Sarah J Neal; Stephanie M McTighe; Guglielmo Roma; Ricardo E Dolmetsch; Jeffrey A Porter; Pico Caroni; Tewis Bouwmeester; Andreas Lüthi; Ivan Galimberti

doi:10.1126/science.aad5487

CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency

Science. 2016 Mar 11;351(6278):1199-203. doi: 10.1126/science.aad5487. Epub 2016 Feb 4.

Authors

Michael Bidinosti¹, Paolo Botta², Sebastian Krüttner², Catia C Proenca¹, Natacha Stoehr¹, Mario Bernhard¹, Isabelle Fruh¹, Matthias Mueller¹, Debora Bonenfant³, Hans Voshol³, Walter Carbone¹, Sarah J Neal⁴, Stephanie M McTighe⁴, Guglielmo Roma¹, Ricardo E Dolmetsch⁴, Jeffrey A Porter¹, Pico Caroni², Tewis Bouwmeester¹, Andreas Lüthi², Ivan Galimberti⁵

Affiliations

¹ Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
² Friedrich Miescher Institute, Basel, Switzerland.
³ Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland.
⁴ Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA.
⁵ Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. [email protected].

PMID: 26847545
DOI: 10.1126/science.aad5487

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.

MeSH terms

Amino Acid Sequence
Animals
Autism Spectrum Disorder / drug therapy*
Autism Spectrum Disorder / enzymology
Autism Spectrum Disorder / genetics
Chromosome Deletion
Chromosome Disorders / genetics
Chromosomes, Human, Pair 22 / genetics
Disease Models, Animal
Down-Regulation
Gene Knockdown Techniques
Humans
Insulin-Like Growth Factor I / metabolism
Mechanistic Target of Rapamycin Complex 1
Mice
Microfilament Proteins
Molecular Sequence Data
Multiprotein Complexes / metabolism
Nerve Tissue Proteins / genetics*
Neurons / enzymology
Phosphorylation
Protein Phosphatase 2 / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Proteomics
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Rats
Signal Transduction
TOR Serine-Threonine Kinases / metabolism

Substances

Microfilament Proteins
Multiprotein Complexes
Nerve Tissue Proteins
Shank3 protein, mouse
insulin-like growth factor-1, mouse
Insulin-Like Growth Factor I
Clk dual-specificity kinases
Protein-Tyrosine Kinases
Mechanistic Target of Rapamycin Complex 1
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Protein Phosphatase 2

Supplementary concepts

Telomeric 22q13 Monosomy Syndrome