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The Journal of Neuroscience, October 1, 2003, 23(26):8955-8966
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Cellular/Molecular
Fine Structure and Biochemical Mechanisms Underlying Nigrostriatal Inclusions and Cell Death after Proteasome Inhibition
Francesco Fornai,1,2
Paola Lenzi,1
Marco Gesi,1
Michela Ferrucci,1
Gloria Lazzeri,1
Carla L. Busceti,2
Riccardo Ruffoli,1
Paola Soldani,1
Stefano Ruggieri,2,3
Maria G. Alessandrì,4 and
Antonio Paparelli1
1Department of Human Morphology and Applied Biology, University of Pisa, I-56100 Pisa, Italy, 2Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Mediterraneo Neuromed Pozzilli, I-86100, Italy, 3Department of Neurological Sciences, University of Rome "La Sapienza," I-00185 Rome, Italy, and 4Instituto di Ricovero e Cura a Carattere Scientifico, Stella Maris Scientific Institute, I-00185 Pisa, Italy
Mutation of genes encoding for various components of a metabolic pathway named the ubiquitin-proteasome system (UP) leads to inherited forms of Parkinson's disease (PD), whereas various components of the UP are constantly present within neuronal inclusions, Lewy bodies, that characterize most genetic and sporadic forms of PD. It has been hypothesized that impairment of this metabolic pathway might be a common mechanism for the onset of PD, and a recent study demonstrated a dysfunction of the UP system within the substantia nigra of patients affected by sporadic PD. In search for the mechanisms underlying the selective toxicity for nigral neurons after inhibition of the UP system, we explored the selective effects after striatal microinfusions of lactacystin or epoxomycin and potential retrograde changes within the ipsilateral substantia nigra. We found that neurotoxicity was selective for striatal dopamine (DA) components and led to retrograde apoptosis within nigral DA cells, which developed neuronal inclusions staining for antigens of the UP system. We found the same ultrastructural features characterizing inclusions obtained in vivo and in vitro after UP inhibition. In vivo, lactacystin-epoxomycin-induced toxicity was suppressed by inhibiting DA synthesis. Similarly, in vitro inclusions and apoptosis were prevented by reducing endogenous DA. On the other hand, toxicity of proteasome inhibition was enhanced by drugs augmenting DA availability: L-3,4-dihydroxyphenylalanine, monoamine oxidase blockers, and DA  -hydroxylase blockers.
These findings demonstrate that impairment of the UP system produces cell death and neuronal inclusions selectively for DA-containing neurons that depend on the occurrence of endogenous DA.
Key words: lactacystin; epoxomycin; neuronal inclusions; nigrostriatal damage; Parkinson's disease; ubiquitin-proteasome pathway;  -synuclein
Received Jan 23, 2003;
revised August 11, 2003;
accepted August 13, 2003.
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