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Proteasome Inhibitor Lactacystin Induces Cholinergic Degeneration

Published online by Cambridge University Press:  02 December 2014

Hai-Yan Zhou ,
Yu-Yan Tan ,
Zhi-Quan Wang ,
Gang Wang ,
Guo-Qiang Lu  and
Sheng-Di Chen
Hai-Yan Zhou
Affiliation:
Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine
Yu-Yan Tan
Affiliation:
Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine
Zhi-Quan Wang
Affiliation:
Institute of Health Science, Shanghai Institutes of Biological Sciences, Chinese Academy of Science & Shanghai Jiaotong University School of Medicine, Shanghai, China
Gang Wang
Affiliation:
Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine
Guo-Qiang Lu
Affiliation:
Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine
Sheng-Di Chen*
Affiliation:
Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine Institute of Health Science, Shanghai Institutes of Biological Sciences, Chinese Academy of Science & Shanghai Jiaotong University School of Medicine, Shanghai, China
*
Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
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Abstract

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Objective:

Ubiquitin proteasome system dysfunction is believed to play an important role in the development of Parkinson's disease (PD), and almost all studies till now have mainly focused on the susceptibility of dopaminergic neurons to proteasome inhibition. However, in fact, there are many other types of neurons such as cholinergic ones involved in PD. In our present study, we attempt to figure out what effect the failure of ubiquitin proteasome function would execute on cholinergic cells in culture.

Methods:

We treated cholinergic cells in culture with various doses of lactacystin. Then MTT assay was used to evaluate the cellular viability and the Annexin V-PI method was used to detect apoptosis. Both cellular soluble and insoluble polyubiquitinated proteins were detected by western blot. Furthermore, the mitochondrial membrane potential was analyzed using JC-1 and the intracellular production of reactive oxygen species (ROS) was determined using the fluorescent probe CM-H2DCFDA.

Results:

We found that low doses of lactacystin were enough to induce significant apoptotic cell death, disturb the mitochondrial membrane potential, and cause oxidative stress. We also found that the amounts of polyubiquitinated proteins dramatically increased with high doses, although the loss of cells did not increase accordingly.

Conclusions:

Our results suggest that cholinergic cells are sensitive to ubiquitin proteasome system dysfunction, which exerts its toxic effect by causing mitochondrial dysfunction and subsequent oxidative stress, not through polyubiquitinated proteins accumulation.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 37 , Issue 2 , March 2010 , pp. 229 - 234
Copyright
Copyright © The Canadian Journal of Neurological 2010

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