Dissecting the early dysregulation of neuronal output in human neurons: an opportunity for a functional rescue of ALS/FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases for which there are currently no cures. Although the mechanisms remain unclear, these diseases ultimately result in the complete degeneration of axons, the long wire-like extensions that neurons use to carry signals to distal synapses and transmit information to other cells. As a result, neurons become unable to communicate with other neurons or muscle cells. However, although this represents a key feature of the disease, recent work suggests that before any structural degeneration, axons show abnormal function that manifests at multiple sites along the long wire-like structure. In other words, axons cease to work properly before they are lost. This proposal aims to systematically investigate and address this axonal dysfunction at an early stage to develop novel therapeutic strategies aimed at recovering proper function, rather than axon loss. The primary objective of this research is to identify the molecular basis of axonal dysfunction in human ALS/FTD neurons and design therapeutic strategies to counteract and recover this dysfunction in the hope of halting disease progression and preventing axon loss. To achieve these goals, we will develop human neurons from induced pluripotent stem cells that carry mutations found in patients with ALS and FTD. By generating motor neurons and growing them with muscle cells, we will create a neuromuscular system to study ALS and, in parallel, by growing excitatory and inhibitory neurons at ratios that resemble those found in the brain, we will establish a neuronal network to study FTD. Armed with these state-of-the-art in vitro systems, we will use a combination of imaging and electrophysiological techniques to characterise altered axon function in ALS/FTD neurons. We will complement the analyses of our ALS and FTD in-a-dish systems described above with in-depth molecular investigations to identify genes that are dysregulated in ALS/FTD and establish how they affect the function of axons. The goal is to pinpoint the culprits underlying axonal dysfunction. Having isolated key target genes, we will establish whether axon dysfunction is responsible for disease progression and, if so, which aspects of this dysfunction are the most relevant. Our overall approach will be to either recover specific aspects of axon function in ALS/FTD neurons or induce dysfunction artificially in neurons without the disease. Finally, with this comprehensive knowledge at hand, we will renormalise the expression of target genes found to be important for key axon functions to prevent the progression of ALS/FTD. These findings will allow us to develop new strategies to recover axon function in ALS/FTD neurons during the early periods of the disease, which may also prevent axon loss and neuronal degeneration. We believe this pre-clinical work could make a significant impact in the development of new therapies for ALS/FTD as well as other neurodegenerative diseases.