Understanding the basis of CSMN vulnerability using a proteomics approach

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitinase that plays a critical role in maintaining free ubiquitin levels in neurons. Patients with mutations in their UCHL1 gene develop motor function defects, paralysis, and upper motor neuron defects. Mice that lack all UCHL1 function (UCHL1nm3419, UCHL1-/-) display motor neuron defects and profound corticospinal motor neuron (CSMN) degeneration characterized by increased ER-stress, vacuolated apical dendrites, and spine loss. These findings show the importance of UCHL1 for CSMN health. Here, we used a bottom-up proteomics approach coupled with UCHL1-immunoprecipitation to reveal the proteins that interact with UCHL1. We then investigated if these interactions were specific to neurons in the motor cortex by including neurons in the spinal cord and trigeminal ganglia (TG). Our initial findings suggest that UCHL1 binds to and interacts with different proteins in the motor cortex, spinal cord, and TG, and this may in part explain why in its absence CSMN display the most prominent cell loss and neuronal vulnerability. CSMN vulnerability is a key component of disease pathology in a number of motor neuron diseases, such as primary lateral sclerosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Understanding the underlying causes of their vulnerability using a proteomics approach will have significant impact on revealing key cellular and molecular pathways responsible for their degeneration.