Restoration of excitation/inhibition balance to modulate motoneron degeneration in ALS

• Applicant: 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: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446067541

Amyotrophic Lateral Sclerosis (ALS) is an invariably fatal motoneuron (MN) disease causing the progressive degeneration of upper and lower motoneurons severely affects voluntary movements, speech and breathing. Median survival after diagnosis is estimated to be 4–5 years. To date, there is neither preventive nor efficient therapeutic approach that can alter disease progression.Multiple genetic murine models have revealed differential vulnerability of MNs to the disease across motor pools, or within each motor pool. It has recently been demonstrated, and the two laboratories involved in this project have largely contributed to this demonstration, that vulnerable MNs experience a reduced excitation before degeneration, and that restoring excitation reduces some disease markers. Thus, loss of MN excitation is a newly appreciated critical step in the degeneration of MNs in ALS.What is the origin of such phenotype and how can it be addressed therapeutically? Preliminary data from the two applicant laboratories clearly show that synaptic inputs to MN are abnormal very early in disease progression and that the dysfunction originates from the disruption of the post-synaptic structures. Our goal is to investigate whether dysfunction of excitatory synapses can be reversed by selective chemogenetic manipulations and to show that restoration of the excitation/inhibition balance re-instates MN firing capacity. This would be a new therapeutic strategy with translational applications.This objective will be achieved by complementary and cutting-edge in vivo technologies that our two laboratories master: advanced AAV vectors and in vivo chemogenetic manipulation of synaptic inputs and intrinsic excitability (Ulm team); in vivo electrophysiological probing of synaptic inputs and MN properties in mice (Paris team). The demonstration of synaptic disturbances as primum movens of the disease would be a significant conceptual advancement, implying that neurodegeneration is actually highly dependent on proper synaptic input, instead of being dependent on biochemical parameters, and can be therefore therapeutically targeted at synaptic level.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professor Dr. Daniel Zytnicki