Year 1

Motor neuron (MN) diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) lead to progressive degeneration of MNs, presenting first with muscle weakness, followed by locomotor defects and frequently death due to respiratory failure. While progress has been made in identifying genes associated with MN degeneration, the molecular and cellular processes underlying disease onset and progression remain unclear, and no effective therapies are available. Our project seeks to identify the underlying causes of MN degeneration, focusing first on SMA, using stem cell-derived motor neurons harboring genetic mutations associated with SMA as a model system. In the first year of our project, we have developed an innovative assay platform for stimulating and recording the activity of stem cell derived motor neurons using optical methods rather than more traditional electrical activity measurements. This modification greatly improves the speed and ease with which motor neuron activity measurements can be made, allowing us to evaluate activity differences at a population level rather than individual cells. This difference is important for discerning subtle disease phenotypes and may serve as the basis for drug screening in the future. With this system, we have identified differences in the manner by which normal and SMA-diseased motor neurons communicate with muscle cells that occur before signs of motor neuron degeneration have occurred. These findings suggest that further insights into SMA pathology may be gained from examining this aspect of motor neuron function in greater detail. Through this approach, we seek to identify novel means for correcting these communication defects to improve motor neuron survival and ultimately patient health.