Prostaglandin J2: Its role in protein aggregation and cytoskeletal integrity

Two fundamental aspects of many neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) are the presence of (1) signs of inflammation and (2) neuronal inclusions containing ubiquitinated protein aggregates. The relationship between these two pathological characteristics and their contribution to neurodegeneration are poorly defined.; This research was undertaken to investigate the impact of a product of inflammation, i.e. prostaglandin J2 (PGJ2), on neuronal homeostasis and on the development of ubiquitinated protein aggregates. We chose to investigate the effects of PGJ2 because it is an endogenous ligand that is a metabolite of PGD2, the most prominent prostaglandin in the mammalian brain.; Our data show that the "inflammatory mediator" PGJ2 (1) compromises an enzymatic activity associated with detoxification pathways thus exacerbating neuronal damage and (2) mediates protein aggregation in neuronal cells by perturbing (a) cytoskeletal integrity and (b) proteasome activity.; In conclusion, these data strongly support the notion that neurotoxic products of inflammation, such as PGJ2, recapitulate many of the pathological processes relevant to neurodegenerative disorders such as AD and PD. Inflammation is thus likely to play a pivotal role in numerous neurodegenerative disorders. Traditional anti-inflammatory drugs that target cyclooxygenase activities have limited therapeutic use in neurodegeneration because of their severe side effects after long-term use. The development of novel anti-inflammatory drugs more specifically aimed at targets downstream from cyclooxygenases may prove to be more effective neuroprotective agents in multiple forms of neurodegenerative diseases.