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CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency

2016; American Association for the Advancement of Science; Volume: 351; Issue: 6278 Linguagem: Inglês

10.1126/science.aad5487

1095-9203

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

Genomics and Rare Diseases

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.