Project Details
Post-synaptic disruption drives motoneuron vulnerability and disease progression in ALS
Subject Area
Molecular and Cellular Neurology and Neuropathology
Clinical Neurology; Neurosurgery and Neuroradiology
Molecular Biology and Physiology of Neurons and Glial Cells
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
Loss of motoneurons (MN) in Amyotrophic Lateral Sclerosis (ALS) has been attributed to excitotoxic damage due to hyperexcitability and resulting in mitochondrial dysfunction, ER stress and autophagy dysfunction. However, recent evidence shows that vulnerable MN are hypoexcitable and unable to fire long before degeneration and that restoring firing capabilities reduces disease burden and delays denervation. The origin of the loss of firing in MN is unknown and it is unclear how this may contribute to neuronal vulnerability; nevertheless, it is known that reduced synaptic input decreases neuronal fitness by limiting the expression of neuroprotective activity-dependent transcriptional programs. We have preliminary demonstrated that postsynaptic structures (in particular, those at the Ia synapses) display morphological and functional signs of disruption. In particular, Shank1-enriched post-synaptic densities at Ia synapses are fragmented and Homer clusters and GluR4 puncta are severely reduced. Are synaptic changes a cause of the disease progression reducing MN excitation, and therefore limiting activity-dependent neuroprotection? To address this point, we plan to perform genetic manipulations that will affect selectively only the synaptic inputs. In detail, we are going to cross mutant SOD1 ALS mouse model with a Shank1 KO: in the resulting double-tg mice, excitatory synapses will be selectively disrupted early on in disease course. We anticipate observing a worsening of disease progression and an acceleration of disease markers appearance and accumulation. In parallel, we will investigate if synaptic derangement is detectable in spinal cord samples from human patients and non-ALS controls. Finally, we will put in place a therapeutic strategy to restore the integrity of the post-synaptic density: we will use AAV vectors to overexpress PSD95 or short Shank1 isoforms specifically in the MN of mutant SOD1 mice. We anticipate verifying an improvement in disease markers burden and a delay in denervation. At the end of the project, we will have demonstrated the causal link between synaptic dysfunction and disease onset and progression in ALS and eventually, we could demonstrate a new approach to treat MN disease by restoring synaptic integrity.
DFG Programme
Research Grants