Inflammatory Stimuli as 'Second-Hit' Triggers for Development of Progressive Nigral Degeneration
Development of Progressive Pre-clinical Models of PD, 2006
Parkin and DJ-1 knockout mice model the recessively inherited loss-of-function mutations in these genes that cause human parkinsonism. Despite significant nigrostriatal dysfunction in both knockout lines and age-dependent increases in markers of lipid and protein oxidation in Parkin knockout brains, age-dependent nigral cell loss does not occur in these mice. This suggests that Parkin and/or DJ-1 knockout mice require a 'second hit' in the form of an environmental toxin to trigger progressive nigral cell loss.
To develop chronic 'second-hit' models of PD with progressive degeneration of the nigrostriatal pathway, we will combine genetic pre-clinical models (Parkin- and DJ-1-deficient mice) with lipopolysaccharide (LPS)- or Tumor Necrosis Factor (TNF)-induced inflammation to mimic the manner in which genetic and environmental factors may contribute to PD in humans. The combination of genetic and environmental factors to trigger nigral degeneration is likely more relevant to PD etiology than the use of either one alone.
Pro-inflammatory mediators such as TNF are likely to be significant early modifiers of genetic factors. Our prediction is that they will influence the fate of stressed and vulnerable Parkin- or DJ-1-deficient neurons and trigger their degeneration. High levels of TNF are evident shortly after administration of neurotoxins used to model PD in rodents and primates and in the CSF and postmortem brains of PD patients.
Functionally, our recent studies indicate that TNF does contribute to progressive degeneration of the nigrostriatal pathway in vivo, since chronic inhibition of soluble TNF signaling in vivo with dominant negative TNF inhibitor proteins rescues a significant fraction of nigral dopaminergic neurons from death. In addition to developing new chronic progressive 'second-hit models' in which to test neuroprotective and neuroregenerative strategies, the immediate impact of these studies will be to provide much needed mechanistic insight on how environmental factors (inflammation caused by toxins, bacterial or viral infections) might modify the known genetic risks for developing PD.
Because post-mortem analyses of brains from individuals bearing DJ-1 mutations have not been reported, the role of inflammation in triggering or contributing to DJ-1-linked Parkinsonism must be determined. For patients bearing Parkin mutations, the age at onset of Parkinsonism can vary significantly, even within families carrying the same mutant alleles. Our studies may provide evidence for specific environmental triggers, such as inflammation, that could account for such variability in age at onset.
The researchers demonstrated that a second inflammatory hit on top of a Parkin deficiency resulted in the development of PD-like pathology and behavioral abnormalities in pre-clinical models. The team also investigated whether this same inflammatory trigger induced nigral degeneration in DJ-1-deficient mice. Surprisingly, it did not, and neither did delivery of intranasal TNF, suggesting that unlike Parkin, DJ-1 does not have a critical role in protecting against inflammation-related nigral degeneration.
Results of this project were published in the journal Neuroscience. Additional results are in preparation for submission to Journal of Neuroinflammation.
Associate Professor of Physiology at Emory University School of Medicine
Location: Atlanta, Georgia, United States
Associate Professor, Department of Neurology at The University of Alabama at Birmingham
Location: Birmingham, Alabama, United States