Role of the proteasome in fly models of neurodegeneration.

Most neurodegenerative disorders are associated with aggregates of ubiquitinated proteins, such as Lewy bodies in Parkinson's disease and neurofibrillary tangles in Alzheimer's disease. Although the etiology of the sporadic forms of these disorders remains elusive, these observations support our idea that proteasome impairment is an important risk factor in neurodegeneration. Proteasome dysfunction is, thus, expected to be a pivotal link between environmental and genetic factors that are implicated in triggering neurodegeneration.

Neurotoxic prostaglandin J2 enhances cyclooxygenase-2 expression in neuronal cells through the p38MAPK pathway: a death wish?

The role of the proinflammatory and inducible form of cyclooxygenases (COX-2) in neurodegeneration is not well defined. Some of its metabolic products, such as prostaglandins (PG) of the J2 series, are known to be neurotoxic. Here we demonstrate that PGJ2 enhances COX-2 gene expression without elevating COX-1 levels in neuronal cells.

Delta12-Prostaglandin J2 inhibits the ubiquitin hydrolase UCH-L1 and elicits ubiquitin-protein aggregation without proteasome inhibition.

To investigate molecular mechanisms linking inflammation with neurodegeneration, we treated neuronal cultures with prostaglandins (PGs), which are mediators of inflammation. PGA1, D2, J2, and Delta12-PGJ2, but not PGE2, reduced the viability and raised the levels of ubiquitinated proteins in the neuronal cells. PGJ2 and its metabolite, Delta12-PGJ2, were the most potent of the four neurotoxic PGs tested in inducing both effects.

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.

N-acetylcysteine and celecoxib lessen cadmium cytotoxicity which is associated with cyclooxygenase-2 up-regulation in mouse neuronal cells.

In many neurodegenerative disorders, aggregates of ubiquitinated proteins are detected in neuronal inclusions, but their role in neurodegeneration remains to be defined. To identify intracellular mechanisms associated with the appearance of ubiquitin-protein aggregates, mouse neuronal HT4 cells were treated with cadmium. This heavy metal is a potent cell poison that mediates oxidative stress and disrupts the ubiquitin/proteasome pathway.