Understanding the role of inflammation in Parkinson’s disease (PD) has attracted a large amount of interest in recent years. Studies have identified various cellular and molecular components of the immune responses that seem to contribute to the pathology associated with α-synuclein accumulation.
We asked Drs. Malú Tansey and David Sulzer to comment on the progress made on characterization of the inflammatory responses that are activated in PD, and on identification of potential targets for neuroprotection. Also we asked Dr. David Standaert to conclude by providing his expert opinion on the significance of these advances for PD therapy.
Prof. Malú Tansey
A great deal of progress has been made in this area (inflammation in PD) since the Edith and Patrick McGeer reported the immunohistological detection of MHC-II-positive microglia in close proximity to neurons and degenerating fibers in the substantia nigra and striatum of PD brains post-mortem, which was clear evidence of activation of innate immune responses in PD. While the original interpretation of this finding was that this activation was merely in response to degenerating and dying neurons, we now recognize that some inflammatory responses likely start prior to neuronal degeneration and in response to synuclein aggregation. In fact, genome-wide association studies (GWAS) have found that the common genetic variation in several antigen-presenting genes (specifically MHC-II expressed in monocytes and microglia) confers slight increases in risk for late onset PD.
Epidemiologically, in collaboration with Beate Ritz and colleagues at UCLA our group found that exposure to common household pesticides synergize with the the high-risk (but not the low-risk) genotype at the HLA-DRA SNP to increase the risk for late onset PD; and functionally, peripheral blood monocytes from individuals homozygous for the high-risk SNP display hyper-responsiveness to immune challenges. Together, these findings suggest that peripheral innate and adaptive immune responses are likely to play a role in PD pathophysiology and that immunomodulation of such responses may represent an opportunity for therapeutic intervention in PD.
Prof. David Sulzer: Recent results indicate that substantia nigra and locus coeruleus neurons themselves could participate in immune system-mediated steps in PD: these neurons present antigen via MHC-I, even in normal individuals, and in PD patient autopsy cases the neurons are sometimes observed to interact with CD8+ cytotoxic T cells. Nevertheless, the genes identified to date to be linked to PD are alleles of MHC-II, not MHC-I, indicating that multiple important steps in this possible mechanism of cell death remain to be elucidated.
Prof. Tansey: There are still unanswered questions regarding the role of inflammation at various stages of the disease in humans. Despite the caveats related to genetic polymorphisms in the peripheral benzodiazepine receptor (upregulated in activated microglia) in human populations that make interpretation of microglia activation by PET imaging a challenge, it is clear that brain inflammation is a typical part of aging and that the extent of inflammation is greater in individuals with PD and involves additional areas known to be affected in the disease. Yet the role of peripheral and central inflammation and immune cell activation in limiting versus advancing disease has not yet been firmly established.
One intriguing hypothesis I would like to put forth is the possibility that prion-like spread of aggregated synuclein is a result of loss of immunocompetence of innate immune cells whose job it is to phagocytose extracellular debris; if they perform this job less and less well as we age, a permissive environment for toxic synuclein propagation would be created. If this turns out to be correct, immunomodulatory agents that reduce production of pro-inflammatory cytokines and enhance phagocytosis by innate immune cells may reduce risk of PD by limiting synuclein transfer between cells.
Prof. Sulzer: One important clue to the activation of microglia stems from the extraordinary ability of neuromelanin and protein aggregates to stimulate these cells as part of the phagocytic process. It may be that the release of synculein aggregates and neuromelanin, neither of which can be effectively degraded by neurons, from dying cells triggers a vicious cycle of local inflammation in the substantia nigra.
Prof. Tansey: Pre-clinical rodent models of nigral degeneration have implicated various inflammatory pathways (including iNOS, TNF, NFkB, JNK) that become chronically activated in progressive loss of vulnerable neuronal populations, as blockade of several different pathways affords neuroprotection. Yet clinical trials using drugs that target several of these pathways have failed in clinical trials, more than likely because they have been tested in patients with significantly advanced disease rather than in earlier stages at which modulation of the inflammatory response could delay the onset of degeneration or slow progression. A good example of the importance of timing is the fact that some but not all epidemiologic studies aimed at analyzing the the risk-lowering effects of NSAIDs show protection: chronic NSAID regimens earlier in life for tennis-elbow and other related chronic injuries are associated with neuroprotective effects whereas NSAID regimens later in life prior to hip replacement surgery are not associated with neuroprotective effects.
Prof. Sulzer: A striking issue in the field has been why so many of the preclinical rodent models that emulate the genetics of PD do not show death of substantia nigra neurons: it is possible that an important factor is the lack of the corresponding effects of the immune system.
Prof. David Standaert: This dialog between two experts, Dr. Tansey and Dr. Sulzer, illustrates the dynamic and rapidly evolving views of the role of inflammation in the etiology and pathogenesis of PD. As Dr. Tansey points out, we have been aware of inflammatory changes in the PD brain for more than 30 years, but it is only recently that investigators have begun to view inflammation as a potential cause rather than a consequence of the disease. Inflammation is a mechanism that can account for the most universal feature of PD, which is its progressive nature. The disease may be triggered by one or more of the mechanisms which have been studied extensively: protein misfolding, oxidative stress, prion-like effects, and others, all driven by interactions between genes and environment. Whatever the proximal trigger (or triggers), inflammation may account for the relentless downhill course once the disease is manifest. For the millions affected by PD today, this could be a critical insight – once the disease is established, treatments modulating the inflammatory response may be the most promising means of slowing its progress.