Characterization of ALS Patient iPSC-Derived Motor Neurons

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disease. It is characterized by motor neuron (MN) degeneration, which leads to the loss of voluntary movement control and premature mortality. Currently, there is no known cure for ALS. Human induced pluripotent stem cells (iPSC) derived from ALS patients have become a powerful tool to study disease mechanisms and identify therapeutic targets. Dr. Rafuse’s lab at Dalhousie University has established several iPSC lines sourced from both healthy individuals and ALS patients harboring the genetic mutations C9ORF72 or TARDBP. In addition, the introduction of Channelrhodopsin-2 (CHR2), a light-sensitive protein, into these cell lines enables the manipulation of cell activity via light stimulation. Using whole-cell patch-clamp, this study aims to systematically characterize MNs derived from these human iPSC lines. My findings revealed that iPSCMNs derived from ALS patients exhibited an aberrant developmental trajectory, characterized by increased maturation rates under harsher culture conditions, abnormal activity patterns, and an early decline in action potential output and synaptic activity compared to healthy controls. Furthermore, chronic optic activation had minor impacts on the healthy control group, but more significantly influenced the development and intrinsic properties of ALS iPSC motor neurons. This presents a potential avenue for modulating cellular behavior at varying developmental stages, thereby potentially extending ALS cell survival.