Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration.
Local axon degeneration is a common pathological feature of many neurodegenerative diseases and peripheral neuropathies. While it is believed to operate with an apoptosis-independent molecular program, the underlying molecular mechanisms are largely unknown. In this study, we used the degeneration of transected axons, termed "Wallerian degeneration," as a model to examine the possible involvement of the ubiquitin proteasome system (UPS). Inhibiting UPS activity by both pharmacological and genetic means profoundly delays axon degeneration both in vitro and in vivo. In addition, we found that the fragmentation of microtubules is the earliest detectable change in axons undergoing Wallerian degeneration, which among other degenerative events, can be delayed by proteasome inhibitors. Interestingly, similar to transected axons, degeneration of axons from nerve growth factor (NGF)-deprived sympathetic neurons could also be suppressed by proteasome inhibitors. Our findings suggest a possibility that inhibiting UPS activity may serve to retard axon degeneration in pathological conditions.
Zhai
Qiwei
Q
Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Wang
Jing
J
Kim
Anna
A
Liu
Qing
Q
Watts
Ryan
R
Hoopfer
Eric
E
Mitchison
Timothy
T
Luo
Liqun
L
He
Zhigang
Z
D000596:Amino Acids / Q000493:pharmacokinetics; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000737:chemistry; D001562:Benzimidazoles / Q000493:pharmacokinetics; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D004533:Egtazic Acid / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D007150:Immunohistochemistry; D007976:Leupeptins / Q000627:therapeutic use; D008870:Microtubules / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009900:Optic Nerve / Q000502:physiology; D020221:Optic Nerve Injuries / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control
D000596:Amino Acids; D001562:Benzimidazoles; D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D014404:Tubulin; D025801:Ubiquitin; C098463:dolaisoleucine; C447680:hoechst 32258; D004533:Egtazic Acid; D020932:Nerve Growth Factor; D010450:Endopeptidases; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C059237:ubiquitin-Nalpha-protein hydrolase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde