Aspects of innate immunity and Parkinson's disease

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.

Keywords: Parkinson’s disease; immunity; mitochondrial dysfunction; synapse dysfunction; ubiquitination.

Figure 1

Innate and adaptive immunity in PD. Innate and adaptive immunity are both thought to affect the cellular response to PD. Both produce cytokines facilitating microglial activation. Innate immune signaling is initiated by PAMP binding. Innate immunity influences cell functions through different organelles, such as the nucleus to affect DNA, the mitochondria and proteasome, and through impacting on synaptic trafficking. Adaptive immunity is a subsequent response. Antigen specific adaptive immune processes occur as immune cells survey the brain. In response to stimuli, B cells secrete IgG and CD4 T cells are activated impacting on selective neuronal degeneration.

Figure 2

Innate immunity and the ubiquitin–proteasome system in PD. Innate immunity is used by the cell to increase proteasome degradation of unwanted proteins by direct and indirect stimulation of the protesome through interferon-γ and ISG15, a ubiquitin-like protein that can be attached to both host and viral proteins. ATM (and appropriately functioning LRRK2) usually stimulates innate immune signaling when necessary. However, ATM also regulates proteasome-mediated protein turnover through suppression of the ISG15 pathway, and together with dysfunctional LRRK2 could decrease proteasome activity necessary for an adequate immune response and the degradation of normal cellular protein substrates, like dimer or tetramer forms of α-synuclein. As these forms are normally degraded through the ubiquitin/proteasome and lysosome/autophagy pathways, along with other cellular substrates, dysfunction in these pathways would increase α-synuclein to form toxic oligomeric species that also inhibit the proteasome and autophagy pathways, as well as innate immunity. This scenario would lead to the increase in toxic oligomers of α-synuclein that aggregate into fibrils to form Lewy bodies over time.

Figure 3

Innate immunity and mitochondria in PD. Many PARK related gene products are located in mitochondria, implicating mitochondrial dysfunction in PD. Interestingly, MAVS/VISA that are attached to the outer membrane of mitochondria are involved in viral infection signaling by activating TRAF6 and TRAF5. Phosphorylation of Iκβα and IRF-3 leads to nuclear translocation of transcription factors and the production of cytokines.

Figure 4

Synaptic trafficking failure and viral intake leading to synaptic dysfunction in PD. Left: The endoplasmic reticulum is composed of a membranous network of tubes and cisternae enclosed in a membrane. It is continuous with the membrane surrounding the nuclear membrane and connects with the Golgi network via the vesicles carrying newly synthesized proteins. Certain vesicle-trafficking steps are required for the translocation of a vesicle from the Golgi apparatus to the plasma membrane. A transport vesicle is tethered and docked at the target membrane to form a tight SNARE complex, thus to merge the vesicle membrane with the target membrane and evacuate neurotransmitters into the extracellular space. The vesicle releasing process is under the assistance of α-synuclein, CDCrel-1, and synaptotagmin. Right: Viruses enter host cells through endosomes. Late endosomes fuse with or convert to lysosomes to degrade its contents, or alternatively it forms budding vesicles that pass to the trans-Golgi region and translocate to the Golgi and endoplasmic reticulum. The endoplasmic reticulum is coated with ribosomes, which assemble the viral amino acids into viral proteins.