Proteasome Inhibitors Protect Against Degeneration of Nigral Dopaminergic Neurons in Hemiparkinsonian Rats

Masatoshi Inden; Jun-ichi Kondo; Yoshihisa Kitamura; Kazuyuki Takata; Kaneyasu Nishimura; Takashi Taniguchi; Hideyuki Sawada; Shun Shimohama

doi:10.1254/jphs.FP0040525

Full Papers

Proteasome Inhibitors Protect Against Degeneration of Nigral Dopaminergic Neurons in Hemiparkinsonian Rats

Masatoshi Inden, Jun-ichi Kondo, Yoshihisa Kitamura, Kazuyuki Takata, Kaneyasu Nishimura, Takashi Taniguchi, Hideyuki Sawada, Shun Shimohama

Author information

Masatoshi Inden
Department of Neurobiology, Kyoto Pharmaceutical University
Jun-ichi Kondo
Department of Neurobiology, Kyoto Pharmaceutical University
Yoshihisa Kitamura
Department of Neurobiology, Kyoto Pharmaceutical University
21st Century COE Program, Kyoto Pharmaceutical University
Kazuyuki Takata
Department of Neurobiology, Kyoto Pharmaceutical University
Kaneyasu Nishimura
Department of Neurobiology, Kyoto Pharmaceutical University
Takashi Taniguchi
Department of Neurobiology, Kyoto Pharmaceutical University
21st Century COE Program, Kyoto Pharmaceutical University
Hideyuki Sawada
Department of Neurology, Graduate School of Medicine, Kyoto University
Shun Shimohama
Department of Neurology, Graduate School of Medicine, Kyoto University

Keywords: proteasome inhibitor, neuroprotection, dopaminergic neuron, substantia nigra, Parkinson’s disease

JOURNAL FREE ACCESS

2005 Volume 97 Issue 2 Pages 203-211

DOI https://doi.org/10.1254/jphs.FP0040525

View "Advance Publication" version (January 30, 2005).

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Abstract

Parkinson’s disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies in the substantia nigra pars compacta (SNpc). α-Synuclein and ubiquitin are components of Lewy bodies, but the process of Lewy body formation and the relationship between inclusion formation and dopaminergic neuronal death have not been resolved. In this study, unilateral intranigral microinjection of 6-hydroxydopamine caused a significant loss of tyrosine hydroxylase-immunopositive neurons in both the substantia nigra and striatum and apomorphine-induced contralateral rotation. The co-administration of proteasome inhibitors, such as lactacystin or carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132), significantly prevented both dopaminergic neurodegeneration and apomorphine-induced rotational asymmetry. Proteasome inhibitors markedly formed intracellular protein inclusions labeled by thioflavin-S in the SNpc. Inclusion-like immunoreactivities for α-synuclein and ubiquitin were detected after 4 weeks. These results suggest that proteasome plays an important role in both the early phase of dopaminergic neuronal death and inclusion body formation.

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