Neurodegeneration: linking ubiquitin/proteasome pathway impairment with inflammation.
Neurodegenerative disorders have been reported to be associated with accumulation of ubiquitinated proteins in neuronal inclusions and also with signs of inflammation. In these disorders, the abnormal protein aggregates may, themselves, trigger the expression of inflammatory mediators, such as, cyclooxygenase 2 (COX-2). Impairment of the ubiquitin/proteasome pathway may contribute to this neurodegenerative process. Accordingly, proteasome inhibitors and oxidative stressors such as cadmium, were found to decrease survival, induce the accumulation of ubiquitinated proteins and elicit up-regulation of cyclooxygenase 2 in neuronal cell cultures. Products of cyclooxygenase 2, such as prostaglandin J2, can, in turn, increase the levels of ubiquitinated proteins and also cause cyclooxygenase 2 up-regulation, creating a "self-destructive" feedback mechanism. In neurodegenerative disorders characterized by neuronal inclusions containing ubiquitinated proteins, a disruption of the ubiquitin/proteasome pathway may, therefore, act in conjunction with cyclooxygenase 2 up-regulation to exacerbate the neurodegenerative process. Cyclooxygenase 2 inhibitors and agents that prevent protein aggregation could be of therapeutic value to these forms of neurodegeneration.
Li
Zongmin
Z
Department of Biological Sciences, Hunter College of CUNY, 695 Park Avenue, New York, NY 10021, USA.
Jansen
Marlon
M
Pierre
Sha-Ron
SR
Figueiredo-Pereira
Maria E
ME
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009097:Multienzyme Complexes; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex