CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency

被引：120

作者：

Bidinosti, Michael ^{[1
]}

Botta, Paolo ^{[3
]}

Kruttner, Sebastian ^{[3
]}

Proenca, Catia C. ^{[1
]}

Stoehr, Natacha ^{[1
]}

Bernhard, Mario ^{[1
]}

Fruh, Isabelle ^{[1
]}

Mueller, Matthias ^{[1
]}

Bonenfant, Debora ^{[2
]}

Voshol, Hans ^{[2
]}

Carbone, Walter ^{[1
]}

Neal, Sarah J. ^{[4
]}

McTighe, Stephanie M. ^{[4
]}

Roma, Guglielmo ^{[1
]}

Dolmetsch, Ricardo E. ^{[4
]}

Porter, Jeffrey A. ^{[1
]}

Caroni, Pico ^{[3
]}

Bouwmeester, Tewis ^{[1
]}

Luthi, Andreas ^{[3
]}

Galimberti, Ivan ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Dev Mol Pathways, Basel, Switzerland

[2] Novartis Inst Biomed Res, Analyt Sci & Imaging, Basel, Switzerland

[3] Friedrich Miescher Inst, Basel, Switzerland

[4] Novartis Inst Biomed Res, Neurosci, Cambridge, MA USA

来源：

SCIENCE | 2016年 / 351卷 / 6278期

关键词：

SCAFFOLDING PROTEIN SHANK3; GROWTH-FACTOR-I; MUTATIONS; MICE; EXPRESSION; BEHAVIORS; ISOFORMS; FAMILY;

D O I：

10.1126/science.aad5487

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, B56b, 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.

引用

页码：1199 / 1203

页数：5

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