iPSC-derived Insights into Motor Neuron Disease and Inflammatory Neuropathies

Abstract

The proper function of the motor circuit is essential for normal interaction as a human being with external cues. While the motor circuit consists of a variety of cell types, one of its core components is the motor neuron itself. Dysfunction of motor neurons is a hallmark of many neuromuscular disorders. Amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and multifocal motor neuropathy (MMN) are just three examples of such disorders. Understanding which molecular mechanisms lead to dysfunction and loss of motor neurons in these diseases is crucial in our aim to develop effective therapies. The rise of iPSC technology and directed differentiation methods has led to many new possibilities in humanized disease modelling, providing a platform to further study these molecular mechanisms. It is important, however, to keep in mind that human iPSC-derived models have their limitations. Therefore, I believe it is essential to see such models as complementary to the vast array other of in vitro, in silico, and in vivo (animal) models which are already at our disposal. In this thesis I describe the results of experiments using iPSC-derived motor neurons, either to identify the underlying molecular mechanisms leading to motor neuron disease, or as a screening tool for autoantibodies involved in immune-mediated disorders. First, we used a combination of cellular, molecular, functional, and ‘omics’ approaches to identify ATXN2-specific effects that lead to motor neuron degeneration in ALS. Second, by using iPSC-derived motor neurons as a disease model for MMN, we showed for the first time that IgM anti-GM1 antibodies are pathogenic, and have both complement-dependent and -independent effects on neurons. Together, these results are a basis for future studies using iPSC-based disease modelling in ALS and MMN, thereby providing a starting point towards identifying novel therapeutic targets. Additionally, we have applied iPSC-derived neurons as a screening tool for IgM anti-GM1 antibodies in MMN and for IgM antibodies in PMA. We showed that the use of iPSC-derived neurons together with synthetic beads be applied successfully for autoantibody detection. Interestingly, our screen of PMA patients revealed a significant subpopulation of patients that may harbour autoantibodies to a previously undetected cell surface antigen, raising the possibility that immunotherapy could be considered for these patients.