Since neurons do not divide, and dilute the cytoplasm with every division, they need to have better controls over their protein content and protein turnover mechanisms. It is not surprising that almost all neurodegenerative diseases display protein accumulations, deposits, and aggregates. Even though the proteins that form aggregates show variation among diseases, there may be some common underlying causes. One of the mechanisms neurons use to control protein turnover is the ubiquitin proteosome system (UPS), which depends on the availability of free ubiquitin. Failure in UPS function results in protein clearance defects, ER-stress, increased autophagy and cellular degeneration. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a unique DUB with both ligase and hydrolase activities and it is gaining much attention after identification of its unique role in maintaining the free ubiquitin levels inside the neurons. Mutations in the UCHL1 gene is linked both to movement disorders in patients with Parkinson's disease, and more recently in early neurodegeneration which involves the upper motor neurons in the cerebral cortex. Building evidence also show reduced levels of UCHL1 protein in the brains of patients with neurodegenerative diseases. In this proposal, we will focus on upper motor neurons, and investigate the role of UCHL1 on the health and stability of this neuron population. We consider upper motor neurons as the "spokesperson"of the cerebral cortex for the motor neuron circuitry, and their degeneration leads to various neurodegenerative diseases such as hereditary spastic paraplegia, primary lateral sclerosis and they degenerate together with spinal motor neurons in amyotrophic lateral sclerosis. This proposal will bring a mechanistic insight into upper motor neuron degeneration and will reveal the role of UCHL1, and more broadly the function of improper UPS on the health and stability of upper motor neurons.
Building evidence suggests the importance of ubiquitin proteasome system (UPS) for maintaining the health and stability of motor neurons, and that UCHL1 is a key regulator of free ubiquitin. We now generated and characterized novel tools to investigate the role and importance of UCHL1 for the health and stability of CSMN both during development and in disease. Our findings will bring a mechanistic insight on motor neuron vulnerability, and will identify novel targets for effective treatment strategies.