Nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition.

Abstract

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.