Restoration of excitation/inhibition balance to modulate motoneron degeneration in ALS
Clinical Neurology; Neurosurgery and Neuroradiology
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
The present project aimed at interfering with ALS-related pathogenesis by modifying the excitation/inhibition balance of motoneurons, hence by controlling the synaptic excitation of motoneurons and the corresponding transcriptional programs. The program originated from the original identification by the two applicant groups of an early downregulation of glutamatergic synaptic responses and reduced excitability of MN. The latter could be corrected by acting on intrinsic excitability thus delivering protective effects on disease pathways. The present project aimed at using chemogenetic systems to restore excitatory synapses through PKA signaling and at using a functionalized intrabody to suppress inhibition. The project has successfully addressed both points and has further extended into the search for translational ways to stimulate PKA signaling in MN. The control of inhibition has successfully delivered a change in disease pathways and further extended into a cooperation on the study of inhibitory synapses in ALS.
Publications
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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
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Diversity of Mammalian Motoneurons and Motor Units. Advances in Neurobiology, 131-150. Springer International Publishing.
Bączyk, Marcin; Manuel, Marin; Roselli, Francesco & Zytnicki, Daniel
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From Physiological Properties to Selective Vulnerability of Motor Units in Amyotrophic Lateral Sclerosis. Advances in Neurobiology, 375-394. Springer International Publishing.
Bączyk, Marcin; Manuel, Marin; Roselli, Francesco & Zytnicki, Daniel
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Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration. Cell Reports, 43(12), 115046.
Nascimento, Filipe; Özyurt, M. Görkem; Halablab, Kareen; Bhumbra, Gardave Singh; Caron, Guillaume; Bączyk, Marcin; Zytnicki, Daniel; Manuel, Marin; Roselli, Francesco; Brownstone, Rob & Beato, Marco
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Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice. openRxiv.
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
