Abstract
Genetic studies on PARK genes have identified dysfunction in proteasomal, lysosomal, and mitochondrial enzymes as pathogenic for Parkinson’s disease (PD). We review the role of these and similar enzymes in mediating innate immune signaling. In particular, we have identified that a number of PARK gene products as well as other enzymes have roles in innate immune signaling as well as DNA repair and regulation, ubiquitination, mitochondrial functioning, and synaptic trafficking. PD enzymatic dysfunction is likely to contribute to inadequate innate immune responses to a variety of extra- and intra-cellular stimuli, with a number of the innate immunity related enzymes found in the characteristic Lewy body pathology of PD. The decrease in innate immunity in PD is associated with an increase in markers of adaptive immunity, and recent GWAS studies have identified variants in human leukocyte antigen region as associated with late-onset sporadic PD (Hamza et al., 2010; Hill-Burns et al., 2011). Intriguing new data also suggest that peripheral immune responses may be involved, giving some potential to alleviate such peripheral dysfunction more directly in patients with PD. It is now important to identify the cell type specific immune responses contributing to the initial changes that occur in PD, as well as to the propagating immune responses important for the progression of PD pathology between cells and within the brain. Overall, a complex interplay between different types of immunity appear to be involved in the underlying pathology of PD.
Highlights
Parkinson’s disease (PD) is the most common progressive movement disorder in the elderly, there is still considerable uncertainty about its etiology
Intriguing new data suggest that peripheral immune responses may be involved, giving some potential to alleviate such peripheral dysfunction more directly in patients with PD
A number of intrinsically driven cellular pathways shown to be dysfunctional in PD are important in mediating innate immune signaling
Summary
Parkinson’s disease (PD) is the most common progressive movement disorder in the elderly, there is still considerable uncertainty about its etiology. Deletions within PINK1 (PARK6) or DJ-1 (PARK7) genes cause aberrant expression of genes involved in the p38 MAP kinase/NF-κB signaling pathway causing changes in the regulation of the innate immune response (Cornejo Castro et al, 2010; Akundi et al, 2011) This suggests that many PARK genes have significant influence on the immune system which may be important for the onset and/or progression of PD. Administration of LPS induces dramatic cell loss in primary neuronal cultures and direct injection of LPS into the substantia nigra produces progressive nigrostriatal degeneration and movement abnormalities in animal models of PD (Liu, 2006; Dutta et al, 2008) These LPS PD models trigger TLR4 mediated signaling pathways (Carvey et al, 2003; Visintin et al, 2003). The expression of CD95 ligand (Fas) has been shown to be important for the capacity
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