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@ARTICLE{Giona:279882,
      author       = {Giona, Federica and Beretta, Stefania and Zippo, Antonio
                      and Stefanoni, Alessia and Tomasoni, Zaira and Vicidomini,
                      Cinzia and Ponzoni, Luisa and Sala, Mariaelvina and Jones,
                      Carrie K and Conn, P Jeffrey and Boeckers, Tobias M and
                      Sala, Carlo and Verpelli, Chiara},
      title        = {{S}hank3 modulates {R}pl3 expression and protein synthesis
                      via m{G}lu5: implications for {P}helan {M}c{D}ermid
                      syndrome.},
      journal      = {Molecular psychiatry},
      volume       = {30},
      number       = {8},
      issn         = {1359-4184},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-00849},
      pages        = {3599 - 3614},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Animals / Nerve Tissue Proteins: metabolism / Nerve Tissue
                      Proteins: genetics / Mice, Knockout / Humans / Mice /
                      Ribosomal Proteins: metabolism / Ribosomal Proteins:
                      genetics / Receptor, Metabotropic Glutamate 5: metabolism /
                      Receptor, Metabotropic Glutamate 5: genetics / Chromosome
                      Disorders: metabolism / Chromosome Disorders: genetics /
                      Protein Biosynthesis / Induced Pluripotent Stem Cells:
                      metabolism / Neurons: metabolism / Chromosomes, Human, Pair
                      22: genetics / Chromosome Deletion / Corpus Striatum:
                      metabolism / Male / Autism Spectrum Disorder: metabolism /
                      Cerebral Cortex: metabolism / Down-Regulation / Disease
                      Models, Animal / Microfilament Proteins / Nerve Tissue
                      Proteins (NLM Chemicals) / Shank3 protein, mouse (NLM
                      Chemicals) / Ribosomal Proteins (NLM Chemicals) / Receptor,
                      Metabotropic Glutamate 5 (NLM Chemicals) / SHANK3 protein,
                      human (NLM Chemicals) / Microfilament Proteins (NLM
                      Chemicals)},
      cin          = {AG Böckers},
      ddc          = {610},
      cid          = {I:(DE-2719)1910002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40089604},
      pmc          = {pmc:PMC12240844},
      doi          = {10.1038/s41380-025-02947-9},
      url          = {https://pub.dzne.de/record/279882},
}