Ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a therapeutic and diagnostic target in neurodegeneration, neurotrauma and neuro-injuries

ABSTRACT

Introduction: Since its discovery as a major CNS-abundant protein 25 years ago, Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has emerged as an important enzyme in regulating brain protein metabolism, by coupling to the proteasome pathway of protein degradation.

Areas covered: UCH-L1 is implicated in both familial and sporadic Parkinson disease and other chronic neurodegenerative diseases. Also, UCH-L1 has been recently emerging as a biofluid-based biomarker for various forms of acute neurotrauma and CNS injury.

Expert opinion: The loss of UCH-L1 activity coupled with the gain of proteinopathy function are linked to neurodegeneration such as Parkinsonism and Alzheimer’s disease. In addition, certain post-translational modifications of UCH-L1 might promote the conversion of the cytosolic UCH-L1(C) to the membrane-associated UCH-L1(M) form, which seems to play a role in alpha-synucleinopathy formation. Thus, targeting the conversion of UCH-L1(C) to the UCH-L1(M) form might be the key to developing therapies for neurodegenerative diseases linked to UCH-L1. In parallel, UCH-L1 is also emerging as a promising neuron-derived biomarker for traumatic brain injury, ischemic and homographic stroke, pediatric hypoxic-ischemic encephalopathy, spinal cord injury, epileptic seizure and cardiac arrest. This shows that UCH-L1 has strong potential as a robust and universal biomarker target for various forms of CNS injury.

KEYWORDS:

• Neurodegeneration
• traumatic brain injury
• brain injury
• Parkinson disease
• diagnostics
• biomarkers
• neurotherapeutics

Article highlights

• The loss of its enzyme activity coupled with the gain of function in terms of protein aggregation/proteinopathy properties of UCH-L1 have been linked to formation of neurodegeneration such as Parkinsonism and Alzheimer’s disease.

• UCH-L1 highly regulated by a range of intracellular post-translational modifications

• There are also two dynamic intracellular pools of UCH-L1 - cytosolic UCH-L1(C) form and the membrane-associated UCH-L1(M) form. Furthermore, UCH-L1(M) form seems to play a role in alpha-synucleinopathy formation.

• Strong clinical and animal data supporting the use of UCH-L1 a promising neuron-derived biomarker for a range of CNS injury conditions. However, across-platform standardization of UCHL1 blood-based assays will needed to be established and made readily accessible.

• Lastly, an under-investigated area is to investigate if there are any direct mechanistic involvement of UCH-L1 in acute and subacute, chronic CNS injury.

This box summarizes key points contained in the article.

Declaration of interest

K. Wang is a shareholder of Banyan Biomarkers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This study is supported in part by NIH grants (R21 NS085455-01 and 1U01 NS086090-01) and DOD grant (W81XWH-14-2-0176) to K. K. Wang. Post-Doctoral support is received from the Fogarty International Training Program in Chronic Non-Communicable Diseases and Disorders at the University of Florida, Grant # 1D43TW009120 to V. Raghavan.