Convergent roles of alpha-synuclein, DA metabolism, and the ubiquitin-proteasome system in nigrostriatal toxicity.
Recent studies disclosed the relevance of specific molecules for the onset of Parkinson's disease (PD) and for the composition of neuronal inclusions. The scenario which is now emerging leads to identify a potential common pathway named the ubiquitin-proteasome (UP) system. In line with this, striatal or systemic inhibiton of the UP system causes experimental Parkinsonism characterized by the formation of neuronal inclusions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is also a complex I inhibitor, has been used for decades to produce experimental Parkinsonism with no evidence for neuronal inclusions in rodents. This leaves open the question whether neuronal inclusions need an alternative mechanism or the inhibition of complex I needs to be carried out continuously to build up inclusions. In the present article, we administered continuously MPTP. In these experimental conditions we compared the neurological consequence of intermittent versus continuous MPTP. In both cases we observed a severe dopamine (DA) denervation and cell loss. However, when MPTP was delivered continuously, spared DA nigral neurons develop ubiquitin, parkin, and alpha-synuclein positive inclusions, which are not detectable after intermittent dosing. The onset of Parkinsonism is associated with inhibition of the UP system. We compared these results with those obtained with amphetamine derivative in vivo and in vitro in which occurrence of neuronal inclusions was associated with inhibition of the UP system and we evaluated the role of DA metabolism in inducing these effects.
Fornai
Francesco
F
Department of Human Morphology and Applied Biology, University of Pisa, Via Roma, 55, I-56126 Pisa, Italy. f.fornai@med.unipi.it
Lazzeri
Gloria
G
Bandettini Di Poggio
Adolfo
A
Soldani
Paola
P
De Blasi
Antonio
A
Nicoletti
Ferdinando
F
Ruggieri
Stefano
S
Paparelli
Antonio
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008694:Methamphetamine / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000209:etiology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism*; D051844:alpha-Synuclein / Q000502:physiology*
D015259:Dopamine Agents; D009498:Neurotoxins; D025801:Ubiquitin; D051844:alpha-Synuclein; D008694:Methamphetamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine