Home > Publications Database > Shank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome. > print

001     279882
005     20250720001618.0
024 7 _ |a 10.1038/s41380-025-02947-9
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024 7 _ |a pmid:40089604
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024 7 _ |a 1359-4184
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024 7 _ |a 1476-5578
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037 _ _ |a DZNE-2025-00849
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Giona, Federica
|b 0
245 _ _ |a Shank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome.
260 _ _ |a [London]
|c 2025
|b Springer Nature
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520 _ _ |a Mutations 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.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a Nerve Tissue Proteins
|2 NLM Chemicals
650 _ 7 |a Shank3 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Ribosomal Proteins
|2 NLM Chemicals
650 _ 7 |a Receptor, Metabotropic Glutamate 5
|2 NLM Chemicals
650 _ 7 |a SHANK3 protein, human
|2 NLM Chemicals
650 _ 7 |a Microfilament Proteins
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: metabolism
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: genetics
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Ribosomal Proteins: metabolism
|2 MeSH
650 _ 2 |a Ribosomal Proteins: genetics
|2 MeSH
650 _ 2 |a Receptor, Metabotropic Glutamate 5: metabolism
|2 MeSH
650 _ 2 |a Receptor, Metabotropic Glutamate 5: genetics
|2 MeSH
650 _ 2 |a Chromosome Disorders: metabolism
|2 MeSH
650 _ 2 |a Chromosome Disorders: genetics
|2 MeSH
650 _ 2 |a Protein Biosynthesis
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: metabolism
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Chromosomes, Human, Pair 22: genetics
|2 MeSH
650 _ 2 |a Chromosome Deletion
|2 MeSH
650 _ 2 |a Corpus Striatum: metabolism
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Autism Spectrum Disorder: metabolism
|2 MeSH
650 _ 2 |a Cerebral Cortex: metabolism
|2 MeSH
650 _ 2 |a Down-Regulation
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Microfilament Proteins
|2 MeSH
700 1 _ |a Beretta, Stefania
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700 1 _ |a Zippo, Antonio
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700 1 _ |a Stefanoni, Alessia
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700 1 _ |a Tomasoni, Zaira
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700 1 _ |a Vicidomini, Cinzia
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700 1 _ |a Ponzoni, Luisa
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700 1 _ |a Sala, Mariaelvina
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700 1 _ |a Jones, Carrie K
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700 1 _ |a Conn, P Jeffrey
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700 1 _ |a Boeckers, Tobias M
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700 1 _ |a Sala, Carlo
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700 1 _ |a Verpelli, Chiara
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773 _ _ |a 10.1038/s41380-025-02947-9
|g Vol. 30, no. 8, p. 3599 - 3614
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|t Molecular psychiatry
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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