Downregulation of Ubiquitin Carboxyl-terminal Hydrolase L1 (UCHL1) Expression in the Pathogenesis of Alzheimers Disease
Received Date: Jul 27, 2018 / Accepted Date: Jul 17, 2018 / Published Date: Jul 30, 2018
The pathogenesis of Alzheimer’s disease (AD) has not been definitely confirmed so far. As a result, a cure for AD is lacking, and current treatments are limited to modest symptomatic relief. Accumulation of damaged proteins and formation of protein aggregates are found in AD brains, suggesting impairment of protein degradation is contained by the pathogenesis of AD. Impairment of ubiquitin-proteasome system has been found in Alzheimer Disease. Here we demonstrate ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) which plays a role in neuronal ubiquitination/deubiquitination machinery participates in the pathogenesis of AD.
Keywords: UCHL1; Alzheimer’s disease; Pathogenesis
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in humans. The brains of patients with Alzheimer’s disease are histopathologically characterized by two hallmark lesions: amyloid‑β‑containing plaques and neurofibrillary tangles (NFTs), implying that something in the degradative systems did not work properly.
Protein ubiquitination/de‑ubiquitination has emerged as an important mechanism for regulating a variety of cellular processes, including protein degradation . Dysfunction of this system, leading to neuronal degeneration by accumulation of damaged protein and formation of protein aggregates , have been reported in the pathogenesis of AD .
Ubiquitin carboxyl‑terminal hydrolase L1 (UCHL1), belonging to a family of deubiquitinating enzymes (DUBs), plays an important role in protein ubiquitination/de‑ubiquitination . It is interesting that AD brains are found to show prominent UCHL1 immunostaining associated with neurofibrillary tangles and levels of soluble Uch‑L1 inversely proportional to the number of tangles . Collectively, these different lines of evidence support a role for UCHL1 in the pathogenesis of AD.
Decreased levels of UCHL1 and AD
It is all known that extracellular amyloid‑β‑containing senile plaques and intracellular neurofibrillary tangles (NFTs) consisting of tau are pathological hallmarks of AD . A possible link between UCHL1 and AD is suggested by reports of decreased levels of UCHL1 in postmortem AD brain and decreased levels of UCHL1 were inversely proportional to tangle numbers . UCHL1 is downregulated in cells exposed to Aβ . Moreover, levels of UCHL1 are decreased in AD model mice . As stated above, levels of UCHL1 are decreased in whether AD patients or AD models (cells and mice).
AD is characterized clinically by progressive memory loss and cognitive impairment. Reduction in memory is confirmed in gracile axonal dystrophy (gad) mice, which do not express UCHL1 . These results imply downregulation of UCHL1 contribute to the progress of AD.
Diminished hydrolase activity and AD
Accumulating findings indicate dysfunction of UCHL1 hydrolase is linked to neurodegenerative disease. The Ile93Met mutation in the UCH‑L1 gene, which leads to 50% reduction in hydrolytic activity, is expected to contribute to the genetic aetiology of PD patients . It’s reported that loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early‑onset progressive neurodegeneration . Oxidative stress‑induced damage becomes much more pronounced in age‑associated pathologies, including AD . Intriguingly, UCHL1 is a target of oxidative damage and the hydrolase activity of oxidative modification of UCHL1 was reduced to about 40–80% . Exogenous wide‑type UCHL1reestablish normal synaptic plasticity and improves associative memory in APP/PS1 mice (AD mice mode), while exogenous C90S mutant UCHL has no function . These results suggest hydrolase activity of UCHL1 could counteract certain symptoms in AD.
Aβ production increase and AD
Aβ is cleaved from amyloid‑β protein precursor (APP) by β-amyloid cleavage enzyme 1 (BACE1) and γ- secretase that exert a range of neurotoxic effects that are considered to be important to the evolution of the pathology. Overexpression of ubiquitin carboxylterminal hydrolase L1 (UCHL1) is observed to decrease Aβ by promoting APP degradation and delays Alzheimer's progression in vivo . BACE1 half-life is reduced in cells overexpressing UCHL1 and decreased Aβ levels are found, while inhibition of UCHL1 significantly increases BACE1 protein level in vitro [8,15]. These researches suggest downregulation of UCHL1 increase Aβ production by impairing APP and BACE1 degradation that contributes to the pathology of AD.
Discussion and Conclusion
A close connection between downregulation of UCHL1 and mechanisms of the pathology of AD is well documented. Some LncRNAs have been detected to have a say in regulating in UCHL1 levels, thus documenting possible mechanisms of decreased UCHL1 levels in AD patients [16-18]. Grape seed procyanidin b2 is observed to increase UCHL1 levels in the research of cardiovascular diseases . Taken together, these findings show that increase of UCHL1 protein levels may be an efficient therapeutic strategy for AD, as well as other neurodegenerative diseases.
We would like to express our gratitude to all those who have helped us during the writing of this thesis. We gratefully acknowledge the help of the members of our lab for many helpful discussions in synthesizing the ideas discussed in this review, we do appreciate their patience, encouragement, and professional instructions during our thesis writing.
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Citation: Shen Y, Zhao Z, You N, Ju R, Pan Z (2018) Downregulation of Ubiquitin Carboxyl-terminal Hydrolase L1 (UCHL1) Expression in the Pathogenesis of Alzheimer’s Disease. Brain Disord Ther 7: 246. DOI: 10.4172/2168-975X.1000246
Copyright: © 2018 Shen Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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