Retrograde dopaminergic neuron degeneration following intrastriatal proteasome inhibition

• Published in: Neuroscience letters 2005-05, Vol.380 (1), p.93-98
• Main Authors: Miwa, Hideto, Kubo, Tomomi, Suzuki, Ai, Nishi, Katsunori, Kondo, Tomoyoshi
• Format: Article
• Language: English
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - toxicity; alpha-Synuclein; Analysis of Variance; Animals; Biological and medical sciences; Cell Count - methods; Cell Death - drug effects; Corpus Striatum - cytology; Cysteine Proteinase Inhibitors - toxicity; Dopamine - metabolism; Dose-Response Relationship, Drug; Functional Laterality; Fundamental and applied biological sciences. Psychology; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Immunohistochemistry - methods; In Situ Nick-End Labeling - methods; Lactacystin; Male; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - metabolism; Oxidative stress; Proteasome; Rat; Rats; Rats, Sprague-Dawley; Retrograde Degeneration - chemically induced; Retrograde Degeneration - metabolism; Substantia nigra; Synucleins; Tyrosine 3-Monooxygenase - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2005.01.024

Recent studies have suggested that defects in the ubiquitin–proteasome system (UPS) contribute to the etiopathogenetic mechanisms underlying dopaminergic neuronal degeneration in Parkinson's disease. The present study aims to study the effects of proteasome inhibition in the nerve terminals of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNpc). Following a unilaterally intrastriatal injection of lactacystin, a selective proteasome inhibitor, dopaminergic neurons in the ipsilateral SNpc progressively degenerated with alpha-synuclein-immunopositive intracytoplasmic inclusions. When lactacystin was administered at a high concentration, the striatum was simultaneously involved, and alpha-synuclein-immunopositive extracytoplasmic granules appeared extensively within the SN pars reticulata (SNpr). In addition, during the retrograde neuron degeneration in SN, the level of heme oxygenase-1 immunopositivity, an oxidative stress marker, was markedly increased in SNpc neurons. These results reveal that intrastriatal proteasome inhibition sufficiently induces retrograde dopaminergic neuronal degeneration with abundant accumulation of alpha-synuclein in the SN.