Molekulare Funktionen der Proteine Shank2 und Shank3 bei der Knochenintegrität und Osteoporose
Gerontobiologie und Geriatrie
Zusammenfassung der Projektergebnisse
Currently, osteoporosis, a major disease of the elderly population, is frequently treated with antiresorptive agents that fail to restore bone formation. Therefore, bone quality is not fully restored. To increase bone quality, novel drug targets that favor bone-forming osteoblasts and their derived osteocytes are required. We identified novel regulators of osteoblast differentiation and function that could also lead to novel targets in the treatment of osteoporosis with siRNA screening in primary osteoblasts. Surprisingly, we discovered through an siRNA screen that genes encoding proteins, previously known for their function for postsynaptic densities in excitatory synapses, ProSAP/Shank proteins, in particular Shank3 and Shank2, are required for osteoblast maturation. Preliminary data from Knockout mice for Shank2/3 indicated a decrease in bone loss. Interestingly, in humans, Shank2/3 mutations (Phelan McDermid syndrome), known to be causative of autism spectrum disorders, lead to craniofacial abnormalities and short stature. Furthermore, we discovered a relocalization of the Shank3 protein from the nucleus in undifferentiated cells to the cytoplasm during differentiation. With a strong translational approach using cell-type-specific mouse strains, state-of-the-art bone phenotyping and analysis of primary cells and iPS cells from Phelan McDermid patients, in this proposal we aimed to uncover the cell-autonomous role of Shank 2 and 3 during osteoblast differentiation and bone formation, as well as the decisive interacting proteins required for this process and the function of relocalization of Shank proteins from the nucleus to the cytoplasm. We finally aimed to rescue human iPS cell-derived osteoblasts and Shank2/3 mutant mice with treatment regimens used for Phelan-McDermid (PMD) syndrome to improve osteoblast function and bone quality. In this ambitious program we achieved a detailed analysis of Shank2/3 deficient mice in the osteoblastic lineage. We observed in this osteoblast-specific deletion a rather mild decrease of bone mass. We focussed for practical reasons during the pandemic on a detailed analysis on Shank2 global deletion, where we observed a strong bone loss in mice, and cell-autonomously an impaired osteoblast mutation, which was strikingly very pronounced at acute knockdown of Shank2 in primary cells and restricted to maturation stages in primary Shank2 knockout cells. Most importantly, this could be transferred to iPS cells derived from patients with PMD syndrome and/or Shank2 loss of function mutation. Furthermore, we found that knockdown of Shank2 interacting proteins strongly impair osteoblast differentiation, suggesting that similar protein networks exist as in post-synaptic structures.
Projektbezogene Publikationen (Auswahl)
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Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications. Journal of Neurodevelopmental Disorders, 13(1).
Delling, Jan Philipp & Boeckers, Tobias M.
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Deletion of the Autism-Associated Protein SHANK3 Abolishes Structural Synaptic Plasticity after Brain Trauma. International Journal of Molecular Sciences, 23(11), 6081.
Urrutia-Ruiz, Carolina; Rombach, Daniel; Cursano, Silvia; Gerlach-Arbeiter, Susanne; Schoen, Michael; Bockmann, Juergen; Demestre, Maria & Boeckers, Tobias M.
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Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice. JBMR Plus, 7(2).
Ahmad, Mubashir; Stirmlinger, Nadine; Jan, Irfana; Stifel, Ulrich; Lee, Sooyeon; Weingandt, Marcel; Kelp, Ulrike; Bockmann, Jürgen; Ignatius, Anita; Böckers, Tobias M. & Tuckermann, Jan
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Shank2/3 double knockout-based screening of cortical subregions links the retrosplenial area to the loss of social memory in autism spectrum disorders. Molecular Psychiatry, 27(12), 4994-5006.
Garrido, Débora; Beretta, Stefania; Grabrucker, Stefanie; Bauer, Helen Friedericke; Bayer, David; Sala, Carlo; Verpelli, Chiara; Roselli, Francesco; Bockmann, Juergen; Proepper, Christian; Catanese, Alberto & Boeckers, Tobias M.
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Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders. Frontiers in Behavioral Neuroscience, 16.
Bauer, Helen Friedericke; Delling, Jan Philipp; Bockmann, Jürgen; Boeckers, Tobias M. & Schön, Michael
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Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice. Molecular Autism, 14(1).
Atanasova, Ekaterina; Arévalo, Andrea Pérez; Graf, Ines; Zhang, Rong; Bockmann, Juergen; Lutz, Anne-Kathrin & Boeckers, Tobias M.
