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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS085161-05
Application #
9298716
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2013-09-15
Project End
2018-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Gautam, Mukesh; Jara, Javier H; Kocak, Nuran et al. (2018) Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology. Acta Neuropathol :
Genç, Bar??; Jara, Javier H; Lagrimas, Amiko K B et al. (2017) Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS. Sci Rep 7:41765
Fil, Daniel; DeLoach, Abigail; Yadav, Shilpi et al. (2017) Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum Mol Genet 26:686-701
Labuzzetta, Charles J; Antonio, Margaret L; Watson, Patricia M et al. (2016) Complementary feature selection from alternative splicing events and gene expression for phenotype prediction. Bioinformatics 32:i421-i429
Jara, J H; Stanford, M J; Zhu, Y et al. (2016) Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex. Gene Ther 23:272-82
Genç, Bar??; Jara, Javier H; Schultz, Megan C et al. (2016) Absence of UCHL 1 function leads to selective motor neuropathy. Ann Clin Transl Neurol 3:331-45
Genç, Bar??; Lagrimas, Amiko Krisa Bunag; Kuru, P?nar et al. (2015) Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line. PLoS One 10:e0132815
Jara, Javier H; Genç, Bar??; Cox, Gregory A et al. (2015) Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function. Cereb Cortex 25:4259-72
Jara, Javier H; Genç, Bar??; Klessner, Jodi L et al. (2014) Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease. Front Neuroanat 8:16