| First Author | Bidinosti M | Year | 2016 |
| Journal | Science | Volume | 351 |
| Issue | 6278 | Pages | 1199-203 |
| PubMed ID | 26847545 | Mgi Jnum | J:231306 |
| Mgi Id | MGI:5770174 | Doi | 10.1126/science.aad5487 |
| Citation | Bidinosti M, et al. (2016) CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency. Science 351(6278):1199-203 |
| abstractText | 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, B56beta, 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. |
