Molecular and Genetic Analysis of Parkin in Microglia Activation and Inflammation-Related Neurodegeneration

Parkinson’s disease (PD) is a progressive, neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Genetic mutations account for only 5-10% of PD cases. Oxidative stress and inflammation have both been linked to sporadic PD. Inflammation-induced injury to dopaminergic neurons can be significantly attenuated by impairment of microglial activation. In addition, previous studies from our lab reported that parkin-/- mice are more susceptible to inflammation-induced degeneration of nigral DA neurons. Therefore, inflammatory responses are a critical determinant of DA neuronal survival.

Microglia support neuronal survival by providing trophic factors and phagocytosing debris. However, with chronic inflammation glia release chemical mediators which are toxic to surrounding neurons. Our data provide evidence that Parkin is a negative regulator of microglial activation. parkin-/- mice display increased cytokine expression in the midbrain and increased cytokines in the serum suggesting parkin-/- mice are basally inflamed.

Parkin loss-of-function mutations are linked to autosomal recessive PD. The parkin gene encodes an E3 ubiquitin ligase linked to mitochondrial dysfunction. Most studies on Parkin concentrate on its role in neurons, however, we hypothesize that Parkin function in microglial activation and inflammatory signaling also affect DA neuron survival. Our biochemical analyses of primary wild type microglia show Parkin expression is negatively regulated by inflammatory stimuli. Pharmacological or genetic inhibition of NF-κB, a transcription factor activated by inflammatory stimulation, blocks the inflammation-induced decrease in Parkin levels. Additionally, our data suggests that NF-κB may bind the parkin promoter, further implicating Parkin function in the inflammatory activation pathway.

These novel findings suggest that in a normal cell experiencing inflammation, the decreased expression of Parkin, which has been shown to antagonize apoptotic signaling cascades, may render the cell more susceptible to death. Additionally, sources of inflammation including environmental triggers, infection, or traumatic injury could cause a normal individual to have the same susceptibility to PD as an individual with an inherited mutation, because inflammation leads to Parkin loss of function.