title: Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions.
abstract: Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death has not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed, and caspase-3 is activated in the affected midbrain. Here we report that a combination of 1-methyl-4-phenylpyridinium ion (MPP(+)) or rotenone and proteasome inhibition causes the appearance of alpha-synuclein-positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP(+)- or rotenone-induced dopaminergic neuronal death. MPP(+) elevated proteasome activity, dephosphorylated mitogen-activating protein kinase (MAPK), and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p42 and p44 MAPK kinase inhibitor. Thus, the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Sakyoku, Kyoto 606-8507, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sawada
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kohno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kihara
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakka
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ibi
authors.forename: Miki
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakamizo
authors.forename: Kentarou
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibasaki
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Inden
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006540:Herbicides / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007477:Ions; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000378:metabolism / Q000494:pharmacology; D051843:Synucleins; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein
chemical_list: D061945:Caspase Inhibitors; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D006540:Herbicides; D007477:Ions; D007976:Leupeptins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C497606:Snca protein, rat; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D012402:Rotenone; C067713:lactacystin; D007770:L-Lactate Dehydrogenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D015655:1-Methyl-4-phenylpyridinium; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine; D000111:Acetylcysteine