Nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition.
OBJECTIVE
We were interested in studying nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition.


METHODS
Observation of progressive behavioral and pathological changes in rats following a unilateral nigral injection of lactacystin, a selective proteasome inhibitor.


RESULTS
After administration at a concentration of 10 microg (2 microl) of lactacystin, when tyrosine hydroxylase (TH) immunostaining decreased gradually in the substantia nigra pars compacta (SNc) and corpus striatum, alpha-synuclein-immunopositive inclusion appeared extensively in the surviving neurons. We also observed the degeneration of diverse cellular organelles by transmission electron microscopy. The effect of cellular organelle degeneration on behavior, a clinical index, was striking and was statistically significant. Over the 3 weeks following the administration of lactacystin, a highly significant decrease in TH immunostaining was observed and alpha-synuclein-immunopositive inclusions gradually appeared. Interestingly, there was a strong correlation in behavioral changes and the increase in alpha-synuclein-immunopositive inclusions whereas the decrease in TH immunostaining did not seem to induce any behavioral changes.


CONCLUSIONS
Our results reveal that unilateral nigral proteasome inhibition induces degeneration in the SNc and corpus striatum as well as behavioral changes demonstrating strong time dependence. Behavioral changes were driven by the formation of alpha-synuclein inclusions, but not by decreased TH neurons.
Niu
Chaoshi
C
Department of Neurosurgery, Anhui Provincial Hospital, Affiliated to Anhui Medical University, Hefei City, Anhui Province, China. niuchaoshi@163.com
Mei
Jiaming
J
Pan
Qi
Q
Fu
Xianming
X
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D018476:Hypokinesia / Q000139:chemically induced / Q000473:pathology; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology*; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D051844:alpha-Synuclein; C067713:lactacystin; D014446:Tyrosine 3-Monooxygenase; D000111:Acetylcysteine