Proteasome inhibition in medaka brain induces the features of Parkinson's disease.

Abstract

Recent findings suggest that a defect in the ubiquitin-proteasome system plays an important role in the pathogenesis of Parkinson's disease (PD). A previous report (McNaught et al. 2004) demonstrated that rats systemically injected with proteasome inhibitors exhibited PD-like clinical symptoms and pathology. However, because these findings have not been consistently replicated, this model is not commonly used to study PD. We used medaka fish to test the effect of systemic administration of proteasome inhibitors because of the high level of accessibility of the cerebrospinal fluid in fish. We injected lactacystin or epoxomicin into the CSF of medaka. With proteasome inhibition in the medaka brain, selective dopaminergic and noradrenergic cell loss was observed. Furthermore, treated fish exhibited reduced spontaneous movement. Treatment with proteasome inhibitors also induced the formation of inclusion bodies resembling Lewy bodies, which are characteristic of PD. Treatment with 6-OHDA also induced dopaminergic cell loss but did not produce inclusion bodies. These findings in medaka are consistent with previous results reporting that non-selective proteasome inhibition replicates the cardinal features of PD: locomotor dysfunction, selective dopaminergic cell loss, and inclusion body formation.

• Authors: Hideaki Matsui, Hidefumi Ito, Yoshihito Taniguchi, Haruhisa Inoue, Shunichi Takeda, Ryosuke Takahashi
• Journal: Journal of neurochemistry (J Neurochem) Vol. 115 Issue 1 Pg. 178-87 (Oct 2010) ISSN: 1471-4159 [Electronic] England
• PMID: 20649841 (Publication Type: Journal Article)
• Copyright: © 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.

Chemical References

• Cysteine Proteinase Inhibitors
• Proteasome Inhibitors
• Sympatholytics
• lactacystin
• Oxidopamine
• Dopamine
• Acetylcysteine
• Norepinephrine

Topics

• Acetylcysteine (analogs & derivatives, cerebrospinal fluid, pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Blotting, Western
• Brain Chemistry (drug effects, physiology)
• Cysteine Proteinase Inhibitors (cerebrospinal fluid, pharmacology)
• Dopamine (physiology)
• Dyskinesia, Drug-Induced (pathology, physiopathology)
• Immunohistochemistry
• Inclusion Bodies (pathology)
• Microscopy, Electron, Transmission
• Neurons (drug effects, metabolism)
• Norepinephrine (physiology)
• Oryzias (physiology)
• Oxidopamine (administration & dosage, cerebrospinal fluid, pharmacology)
• Parkinson Disease, Secondary (chemically induced, pathology, psychology)
• Proteasome Inhibitors
• Swimming (physiology)
• Sympatholytics (administration & dosage, cerebrospinal fluid, pharmacology)
• Ubiquitination (drug effects)