Year 5

Neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig’s disease), affect an increasing proportion of our population as the median age increases. There are no cures for any of these disorders. One reason for the absence of cures has been the absence of good models to understand how neurodegeneration happens.

Genetic studies have identified many of the genes involved in neurodegeneration. To understand how these mutations lead to motor neuron degeneration in ALS, we have creased embryonic stem cells (ESCs) that contain the human ALS-associated mutations. We have also created mice that express these human ALS-associated mutations. We studied motor neurons derived from the ESCs and the mutant mice and found that motor neurons with ALS-associated mutations die at increased rates. We identified proteins that interact with normal and disease-associated proteins. We identified that mutant proteins showed different interactions than normal proteins. After several decades of life, the loss of neurons surpasses compensatory mechanisms, leading to the emergence of symptoms.