Time-resolved single-cell analysis of neural cell differentiation in motor neuron disease

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Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease that is caused by the selective degeneration of the upper and lower motor neurons that eventually leads to paralysis. It is still elusive why motor neurons are so vulnerable, how early disease associated changes appear, and precisely how other supporting cells contribute to the disease.In this project we will investigate and characterise the earliest stages of the disease while focusing on specific cell types and genetic backgrounds. More specifically, we will be utilising induced pluripotent stem cells (iPSCs) from two familial ALS cohorts, sporadic cases of ALS and age-matched controls. These iPSCs will then be differentiated into motor neurons and astrocytes, with single cell RNA sequencing and protein-based assays then employed at key stages of the cell differentiations. In this way, we will be able to elucidate when the earliest disease associated changes occur and identify the key molecular changes relevant to the different cohorts. Together this will provide a time-resolved analysis of the earliest stages of disease using a clinically relevant human model system. Moreover, we will better understand at which stage diverse cell types become vulnerable in relation to diverse disease relevant genetics. Together this information will then be used to test putative therapeutic interventions at the early stages of the disease.