Potential of Stem Cell-Derived Motor Neurons for Modeling Amyotrophic Lateral Sclerosis (ALS)

Abstract

The human motor system comprises the same basic functional and anatomic categories that have been described in vertebrate model systems. However, almost all of the genetic and molecular information about the development of the motor system and motor neuron subtypes is based on studies in animal models, since human motor neurons have been available only in postmortem samples. With the establishment of human embryonic stem (hES) cells as a research tool, and the demonstration that they could be directed to differentiate into spinal motor neurons, this inaccessibility has changed. Spinal motor neurons are the target of several diseases. As one key example, the progressive paralysis and ultimate death of patients with amyotrophic lateral sclerosis (ALS) reflect changes in motor neuron excitability, selective degeneration of nerve-muscle contacts and finally cell death of vulnerable motor neurons. However, the mechanisms of selective motor neuron degeneration are not well understood and there are no effective therapies. The derivation of induced pluripotent stem (iPS) cells from ALS patients allows human motor neurons and other disease-relevant cell types with the same genetic make-up as the patient to be generated in large numbers. However, before they can be reliably used for mechanistic studies or to establish ALS-relevant screens, they need to be validated as a tool. In this article, we discuss salient aspects of human development and neurodegeneration and consider how they can inform our design of appropriate cell models. In addition, we review our recent data suggesting that human iPS cell-derived motor neurons constitute a robust basis for disease modeling and we discuss some of the technological challenges that nevertheless remain to be addressed.