Failure of proteasome inhibitor administration to provide a model of Parkinson's disease in rats and monkeys.
McNaught and colleagues reported recently that systemic administration of proteasome inhibitors PSI (Z-Ileu-Glu(OtBu)-Ala-Leu-CHO) or epoxomicin recapitulated many of the degenerative changes seen in Parkinson's disease including loss of striatal dopamine and cell loss in the substantia nigra, locus ceruleus, dorsal motor nucleus of the X cranial nerve, and nucleus basalis of Meynert. Intracytoplasmic inclusions resembling Lewy bodies were also described. All experiments administering PSI to rats using identical procedures and multiple attempts failed to induce any of the previously described changes. Furthermore, administration of PSI or epoxomicin to monkeys in an attempt to extend the model to a primate species failed. Currently, systemic proteasome inhibition is not a reliable model for Parkinson's disease.
Kordower
Jeffrey H
JH
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. jkordowe@rush.edu
Kanaan
Nicholas M
NM
Chu
Yaping
Y
Suresh Babu
Rangasamy
R
Stansell
James
J
Terpstra
Brian T
BT
Sortwell
Caryl E
CE
Steece-Collier
Kathy
K
Collier
Timothy J
TJ
D000818:Animals; D001921:Brain / Q000473:pathology; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D007150:Immunohistochemistry; D007794:Lameness, Animal / Q000139:chemically induced / Q000473:pathology; D008124:Locomotion / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D009842:Oligopeptides / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D051844:alpha-Synuclein; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase