Chronic inflammation is a critical factor in the pathogenesis of Parkinson's disease (PD). Neuronal and glial prostaglandins mediate proinflammatory responses, but there is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote neurodegeneration. We propose studies to address this crucial omission. We will focus on inflammatory cyclopentenone prostaglandins, such as prostaglandin J2 (PGJ2), because they are potently neurotoxic. Our working hypothesis is that the """"""""inflammatory mediator"""""""" PGJ2 plays a critical role in initiating progressive PD neurodegeneration. PGJ2 is derived spontaneously from PGD2, the major prostaglandin in the mammalian CNS. PGJ2 is a highly reactive and neurotoxic prostaglandin. PGJ2 is unique among the prostaglandin family because it covalently reacts with free sulfhydryls of glutathione and cysteine residues in cellular proteins, thus it is present in vivo primarily as Michael conjugates. Electrophile binding (S-alkylation) by endogenous compounds such as PGJ2 is regarded as playing an important role in determining whether neurons will live or die. We propose that this covalent protein modification by PGJ2 in the brain represents a novel pathogenic post-translational modification and plays a critical role in PD neurodegeneration.
SPECIFIC AIM #1 : Examine how PGJ2 causes ubiquitin/1-synuclein aggregation &its role in cell death Lewy bodies (LB) are a pathologic hallmark of PD. The major LB components are ubiquitinated proteins and 1-synuclein. The mechanisms leading to protein aggregation and its role in PD neurodegeneration remain unclear. We will investigate mechanisms induced by PGJ2 that lead to aggregation of ubiquitinated proteins/1- synuclein and cell death in (a) human dopaminergic-like neuroblastoma SK-N-SH cells, (b) rat ventral midbrain (dopaminergic) and (c) cortical neuronal cultures. Our experimental approach includes pharmacological manipulations and diminishing 1-synuclein expression by siRNA. These studies will characterize mechanisms by which PGJ2 causes PD neurodegeneration.
SPECIFIC AIM #2 : Characterize and optimize our novel PGJ2-induced model of Parkinson's disease The neuroinflammation hypothesis for PD is well accepted. However, there is still a profound gap in our understanding of how products of inflammation promote PD neurodegeneration. We established the first strong model in which an endogenous highly reactive product of inflammation, PGJ2, convincingly induces PD pathology. Our novel PGJ2-induced PD model strongly supports the hypothesis that localized and chronic production (by neurons and/or glia) of highly reactive and neurotoxic cyclopentenone PGJ2 establishes a link between neuroinflammation and PD neurodegeneration. By elucidating the neurotoxic events mediated by prostaglandins, we will be opening up new and important possible targets for pharmaceutical treatment of PD.
Chronic inflammation is a critical factor in the pathogenesis of Parkinson's disease (PD). The studies proposed in this application will elucidate mechanisms, such as alterations in intracellular protein turnover, by which products of inflammation contribute to neuronal injury. These studies are highly significant because a better understanding of the mechanisms by which products of inflammation mediate neuronal injury will lead to more effective anti-inflammatory therapeutic strategies for neurodegenerative disorders, such as PD that are associated with chronic inflammation.
