Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition.
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 beta-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.
Fornai
Francesco
F
Department of Human Morphology and Applied Biology, University of Pisa, I-56100 Pisa, Italy. f.fornai@med.unipi.it
Lenzi
Paola
P
Gesi
Marco
M
Ferrucci
Michela
M
Lazzeri
Gloria
G
Busceti
Carla L
CL
Ruffoli
Riccardo
R
Soldani
Paola
P
Ruggieri
Stefano
S
Alessandri
Maria G
MG
Paparelli
Antonio
A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D016923:Cell Death; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009842:Oligopeptides / Q000633:toxicity; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D015102:3,4-Dihydroxyphenylacetic Acid; C067713:lactacystin; D014446:Tyrosine 3-Monooxygenase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine; D000111:Acetylcysteine; C078846:epoxomicin