Characterization of chronic low-level proteasome inhibition on neural homeostasis.
Increasing evidence suggests that proteasome inhibition plays a causal role in promoting the neurodegeneration and neuron death observed in multiple disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The ability of severe and acute inhibition of proteasome function to induce neuron death and neuropathology similar to that observed in AD and PD is well documented. However, at present the effects of chronic low-level proteasome inhibition on neural homeostasis has not been elucidated. In order to determine the effects of chronic low-level proteasome inhibition on neural homeostasis, we conducted studies in individual colonies of neural SH-SY5Y cells that were isolated following continual exposure to low concentrations (100 nm) of the proteasome inhibitor MG115. Clonal cell lines appeared morphologically similar to control cultures but exhibited significantly different rates of both proliferation and differentiation. Elevated levels of protein oxidation and protein insolubility were observed in clonal cell lines, with all clonal cell lines being more resistant to neural death induced by serum withdrawal and oxidative stress. Interestingly, clonal cell lines demonstrated evidence for increased macroautophagy, suggesting that chronic low-level proteasome inhibition may cause an excessive activation of the lysosomal system. Taken together, these data indicate that chronic low-level proteasome inhibition has multiple effects on neural homeostasis, and suggests that studying the effects of chronic low-level proteasome inhibition may be useful in understanding the relationship between protein oxidation, protein insolubility, proteasome function, macroautophagy and neural viability in AD and PD.
Ding
Qunxing
Q
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536-0230, USA. Jnke110@pop.uky.edu
Dimayuga
Edgardo
E
Martin
Sarah
S
Bruce-Keller
Annadora J
AJ
Nukala
Vidya
V
Cuervo
Ana Maria
AM
Keller
Jeffrey N
JN
D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001798:Blood Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D013995:Time; D025801:Ubiquitin / Q000378:metabolism
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D016877:Oxidants; D011506:Proteins; D025801:Ubiquitin; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex