Proteasome inhibitor lactacystin induces cholinergic degeneration

Hai Yan Zhou, Yu Yan Tan, Zhi Quan Wang, Gang Wang, Guo Qiang Lu, Sheng Di Chen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)229-234
Number of pages6
JournalCanadian Journal of Neurological Sciences
Volume37
Issue number2
DOIs
StatePublished - Mar 1 2010

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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