Bidinosti, Michael, Botta, Paolo, Moreira Ramos Proenca, Catia, Stoehr, Natacha, Bernhard, Mario, Fruh, Isabelle, Mueller, Matthias, Bonenfant, Debora, Voshol, Johannes, Carbone, Walter, Neal, Sarah, Mctighe, Stephanie, Roma, Guglielmo, Dolmetsch, Ricardo, Porter, Jeffrey, Caroni, Pico, Bouwmeester, Antonius, Lüthi, Andreas and Galimberti, Ivan (2016) CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency. Science.

Abstract

SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Downregulation 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.

Item Type:	Article
Keywords:	Autism, Shank3, PI3K-Akt-mTORC1 signaling, CLK2
Date Deposited:	25 Feb 2016 00:45
Last Modified:	25 Feb 2016 00:45
URI:	https://oak.novartis.com/id/eprint/25820