Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions.
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.
Sawada
Hideyuki
H
Department of Neurology, Graduate School of Medicine, Sakyoku, Kyoto 606-8507, Japan.
Kohno
Ryuichi
R
Kihara
Takeshi
T
Izumi
Yasuhiko
Y
Sakka
Noriko
N
Ibi
Masakazu
M
Nakanishi
Miki
M
Nakamizo
Tomoki
T
Yamakawa
Kentarou
K
Shibasaki
Hiroshi
H
Yamamoto
Noriyuki
N
Akaike
Akinori
A
Inden
Masatoshi
M
Kitamura
Yoshihisa
Y
Taniguchi
Takashi
T
Shimohama
Shun
S
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
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