Decoding motor neuron resilience, vulnerability, regeneration and communication in amyotrophic lateral sclerosis to develop neuroprotective therapeutic strategies

Amyotrophic lateral sclerosis (ALS) is defined by the loss of motor neurons (MNs) that innervate voluntary muscles, leading to paralysis.

MNs follow a dying-back pattern in ALS with their synapses with muscle, the neuromuscular junctions (NMJs) and distal axon being early pathological targets. The mechanisms governing this process are largely unknown. Mutations in genes that encode RNA-binding proteins, and thus control RNA metabolism, e.g.

TDP-43 and FUS, have emerged as critical determinants of ALS. Why and how these genes selectively affect MNs in ALS is not clear as they are broadly expressed.

Furthermore, certain MNs are for unknown reasons relatively resistant to degeneration in ALS and even sprout during disease. We aim to unravel the molecular mechanisms of MN vulnerability, resistance and regeneration in ALS.

Towards this goal we will use spatial single cell RNA sequencing and epigenetic profiling of human tissues, CRISPR/Cas9 genome editing of human induced pluripotent stem cells (iPSCs) followed by single cell and axon RNA sequencing to unravel cell intrinsic properties of resistant and vulnerable MNs and their response to disease across mutations.

We will also use an advanced in vitro model of the human NMJ to study cell-cell communication between MNs and muscle in health and early dysregulation in ALS.

Finally, we will modulate genes of interest to improve neuronal resilience and connectivity as well as prolong life-span of transgenic ALS mice using gene therapy.