Post-synaptic disruption drives motoneuron vulnerability and disease progression in ALS

• Applicants: Professor Dr. Tobias Böckers; Professor Francesco Roselli, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431995586

• Final Report Year: 2024

Final Report Abstract

The goal of the present project was to demonstrate the existence of synaptic damage in the motoneurons of ALS patients and mouse models and to demonstrate that interventions at synaptic level could be beneficial on disease-related manifestations. We have indeed demonstrated extensive synaptic loss in spinal cords from human ALS patients; synaptic loss related to disease duration and site of onset. We have also used murine models to demonstrate that enhancing synaptic integrity through activation of PKA signaling (or increasing excitation) through chemogenetics led to decreased disease markers burden, pointing toward an overall beneficial effect. However, activation of PKA through endogenous receptors provided only temporary effects on motoneuron physiology, due to rapid adaptation through downregulation of the receptors. Similar synaptic phenotypes were detected also in motoneurons derived from iPSC obtained from genetic ALS patients; also in this case, modulation of motoneuron excitation normalized synaptic structures and numbers.

Publications

• Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles. Science Translational Medicine, 12(547).
  Lutz, Anne-Kathrin; Pfaender, Stefanie; Incearap, Berra; Ioannidis, Valentin; Ottonelli, Ilaria; Föhr, Karl J.; Cammerer, Judith; Zoller, Marvin; Higelin, Julia; Giona, Federica; Stetter, Maximilian; Stoecker, Nicole; Alami, Najwa Ouali; Schön, Michael; Orth, Michael; Liebau, Stefan; Barbi, Gotthold; Grabrucker, Andreas M.; Delorme, Richard ... & Boeckers, Tobias M.
  
• Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS. Journal of Experimental Medicine, 217(8).
  Bączyk, Marcin; Alami, Najwa Ouali; Delestrée, Nicolas; Martinot, Clémence; Tang, Linyun; Commisso, Barbara; Bayer, David; Doisne, Nicolas; Frankel, Wayne; Manuel, Marin; Roselli, Francesco & Zytnicki, Daniel
  
• Synaptic disruption and CREB‐regulated transcription are restored by K + channel blockers in ALS. EMBO Molecular Medicine, 13(7).
  Catanese, Alberto; Rajkumar, Sandeep; Sommer, Daniel; Freisem, Dennis; Wirth, Alexander; Aly, Amr; Massa‐López, David; Olivieri, Andrea; Torelli, Federica; Ioannidis, Valentin; Lipecka, Joanna; Guerrera, Ida Chiara; Zytnicki, Daniel; Ludolph, Albert; Kabashi, Edor; Mulaw, Medhanie A.; Roselli, Francesco & Böckers, Tobias M.
  
• 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.
  
• 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.
  
• 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
  
• 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.
  
• Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection. Nature Communications, 14(1).
  Li, Shun; Olde Heuvel, Florian; Rehman, Rida; Aousji, Oumayma; Froehlich, Albrecht; Li, Zhenghui; Jark, Rebecca; Zhang, Wanhong; Conquest, Alison; Woelfle, Sarah; Schoen, Michael; O.´Meara, Caitlin C.; Reinhardt, Richard Lee; Voehringer, David; Kassubek, Jan; Ludolph, Albert; Huber-Lang, Markus; Knöll, Bernd; Morganti-Kossmann, Maria Cristina ... & Roselli, Francesco
  
• Patterns of synaptic loss in human amyotrophic lateral sclerosis spinal cord: a clinicopathological study. Acta Neuropathologica Communications, 11(1).
  Aousji, Oumayma; Feldengut, Simone; Antonucci, Stefano; Schön, Michael; Boeckers, Tobias M.; Matschke, Jakob; Mawrin, Christian; Ludolph, Albert C.; Del Tredici, Kelly; Roselli, Francesco & Braak, Heiko
  
• Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model. Molecular Autism, 14(1).
  Olde, Heuvel Florian; Ouali, Alami Najwa; Aousji, Oumayma; Pogatzki-Zahn, Esther; Zahn, Peter K.; Wilhelm, Hanna; Deshpande, Dhruva; Khatamsaz, Elmira; Catanese, Alberto; Woelfle, Sarah; Schön, Michael; Jain, Sanjay; Grabrucker, Stefanie; Ludolph, Albert C.; Verpelli, Chiara; Michaelis, Jens; Boeckers, Tobias M. & Roselli, Francesco
  
• Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.
  Antonucci, Stefano; Caron, Guillaume; Dikwella, Natalie; Krishnamurty, Sruthi Sankari; Harster, Anthony; Zarrin, Hina; Tahanis, Aboud; Heuvel, Florian olde; Danner, Simon M.; Ludolph, Albert C.; Grycz, Kamil; Bączyk, Marcin; Zytnicki, Daniel & Roselli, Francesco