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Could Dysregulation of UPS be a Common Underlying Mechanism for Cancer and Neurodegeneration? Lessons from UCHL1

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Abstract

Ubiquitin proteasome system (UPS) determines the timing and extent of protein turnover in cells, and it is one of the most strictly controlled cellular mechanisms. Lack of proper control over UPS is attributed to both cancer and to neurodegenerative diseases, yet in different context and direction. Cancerous cells have altered cellular metabolisms, uncontrolled cellular division, and increased proteasome activity. The specialized function prevent neurons from undergoing cellular division but allow them to extend an axon over long distances, establish connections, and to form stable neuronal circuitries. Neurons heavily depend on the proper function of the proteasome and the UPS for their proper function. Reduction of UPS function in vulnerable neurons results in protein aggregation, increased ER stress, and cell death. Identification of compounds that selectively block proteasome function in distinct set of malignancies added momentum to drug discovery efforts, and deubiquitinases (DUBs) gained much attention. This review will focus on ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a DUB that is attributed to both cancer and neurodegeneration. The potential of developing effective treatment strategies for two major health problems by controlling the function of UPS opens up new avenues for innovative approaches and therapeutic interventions.

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Acknowledgments

This study was supported by Les Turner ALS Foundation, Wenske Foundation, and Brain Research Foundation Grants (P.H.O.). J.H.J. is supported by ALSA Safenowitz postdoctoral fellowship. The authors thank Dr. Baris Genc and Michael Tu for comments and critical reading of the manuscript.

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  1. Davee Department of Neurology and Clinical Neurological Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Javier H. Jara & P. Hande Özdinler

  2. Northwestern University Integrated Neuroscience (NUIN) Program, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Dominic D. Frank & P. Hande Özdinler

  3. Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL, 60611, USA

    P. Hande Özdinler

  4. Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University, Chicago, IL, 60611, USA

    P. Hande Özdinler

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  1. Javier H. Jara
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Jara, J.H., Frank, D.D. & Özdinler, P.H. Could Dysregulation of UPS be a Common Underlying Mechanism for Cancer and Neurodegeneration? Lessons from UCHL1. Cell Biochem Biophys 67, 45–53 (2013). https://doi.org/10.1007/s12013-013-9631-7

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