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000279882 1001_ $$aGiona, Federica$$b0
000279882 245__ $$aShank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome.
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000279882 520__ $$aMutations or deletions in the SHANK3 gene have been identified in up to 1% of autism spectrum disorder cases and are considered the primary cause of neuropsychiatric symptoms in Phelan McDermid syndrome (PMS). While synaptic dysfunctions have been extensively documented in the absence of Shank3, other mechanisms through which Shank3 may regulate neuronal functions remain unclear. In this study, we report that the ribosomal protein Rpl3 and overall protein synthesis are downregulated in the cortex and striatum of Shank3 knockout (KO) mice and in neurons differentiated from human-induced pluripotent stem cells (hiPSCs) derived from a PMS patient. Moreover, restoring Rpl3 expression in the striatum of Shank3 KO mice was sufficient to rescue protein synthesis and mitigate excessive grooming, suggesting that the behavioral alterations observed in Shank3 KO mice might be, at least in part, caused by Rpl3 downregulation and consequent impaired protein synthesis. Furthermore, we demonstrated that chronic inhibition of mGlu5 is sufficient to reduce Rpl3 expression, which in turn impairs global protein synthesis. Consequently, chronic treatment with VU0409551, a potent and selective mGlu5 positive allosteric modulator, rescues Rpl3 expression and the resulting reduction in protein synthesis, leading to long-lasting improvements in behavioral deficits in Shank3 KO mice Altogether, we propose a new role for Shank3 in modulating Rpl3 protein expression, ribosomal function, and protein synthesis by downregulating mGlu5 receptor activity.
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000279882 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000279882 650_7 $$2NLM Chemicals$$aShank3 protein, mouse
000279882 650_7 $$2NLM Chemicals$$aRibosomal Proteins
000279882 650_7 $$2NLM Chemicals$$aReceptor, Metabotropic Glutamate 5
000279882 650_7 $$2NLM Chemicals$$aSHANK3 protein, human
000279882 650_7 $$2NLM Chemicals$$aMicrofilament Proteins
000279882 650_2 $$2MeSH$$aAnimals
000279882 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000279882 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000279882 650_2 $$2MeSH$$aMice, Knockout
000279882 650_2 $$2MeSH$$aHumans
000279882 650_2 $$2MeSH$$aMice
000279882 650_2 $$2MeSH$$aRibosomal Proteins: metabolism
000279882 650_2 $$2MeSH$$aRibosomal Proteins: genetics
000279882 650_2 $$2MeSH$$aReceptor, Metabotropic Glutamate 5: metabolism
000279882 650_2 $$2MeSH$$aReceptor, Metabotropic Glutamate 5: genetics
000279882 650_2 $$2MeSH$$aChromosome Disorders: metabolism
000279882 650_2 $$2MeSH$$aChromosome Disorders: genetics
000279882 650_2 $$2MeSH$$aProtein Biosynthesis
000279882 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000279882 650_2 $$2MeSH$$aNeurons: metabolism
000279882 650_2 $$2MeSH$$aChromosomes, Human, Pair 22: genetics
000279882 650_2 $$2MeSH$$aChromosome Deletion
000279882 650_2 $$2MeSH$$aCorpus Striatum: metabolism
000279882 650_2 $$2MeSH$$aMale
000279882 650_2 $$2MeSH$$aAutism Spectrum Disorder: metabolism
000279882 650_2 $$2MeSH$$aCerebral Cortex: metabolism
000279882 650_2 $$2MeSH$$aDown-Regulation
000279882 650_2 $$2MeSH$$aDisease Models, Animal
000279882 650_2 $$2MeSH$$aMicrofilament Proteins
000279882 7001_ $$0P:(DE-2719)9001978$$aBeretta, Stefania$$b1$$eFirst author$$udzne
000279882 7001_ $$00000-0001-8421-7554$$aZippo, Antonio$$b2
000279882 7001_ $$aStefanoni, Alessia$$b3
000279882 7001_ $$aTomasoni, Zaira$$b4
000279882 7001_ $$aVicidomini, Cinzia$$b5
000279882 7001_ $$aPonzoni, Luisa$$b6
000279882 7001_ $$00000-0001-9310-958X$$aSala, Mariaelvina$$b7
000279882 7001_ $$aJones, Carrie K$$b8
000279882 7001_ $$aConn, P Jeffrey$$b9
000279882 7001_ $$0P:(DE-2719)2812855$$aBoeckers, Tobias M$$b10
000279882 7001_ $$0P:(DE-2719)9000735$$aSala, Carlo$$b11$$udzne
000279882 7001_ $$0P:(DE-2719)9000803$$aVerpelli, Chiara$$b12$$udzne
000279882 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-025-02947-9$$gVol. 30, no. 8, p. 3599 - 3614$$n8$$p3599 - 3614$$tMolecular psychiatry$$v30$$x1359-4184$$y2025
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