In our last Insights article, we discussed the relationship between a variety of gastrointestinal conditions and the risk of Parkinson’s disease. The “gut-first” theory of Parkinson’s was originally proposed over 20 years ago, and the role of the immune system—with the gastrointestinal tract as a potential point of entry—in the pathogenesis of Parkinson’s disease is an increasing focus of research.
The immune system is our body’s line of defense against external threats such as viruses and toxins. Parkinson’s disease may be triggered by the body’s immune system responding to misfolded alpha-synuclein in the brain as well as in the periphery. Upregulation of alpha-synuclein levels is a normal response to infection. Dysregulated inflammatory responses, possibly due to genetic predisposition or aging, may cause monomeric alpha-synuclein to form oligomers that are taken up by nerve endings and undergo axonal transport to the central nervous system, where they can aggregate into pathogenic fibrils. This process can trigger neurodegeneration, leading to synucleinopathies. Increasingly, research is pointing toward the immune system’s response causing more acute damage to the neurons than the internal deposits of misfolded alpha-synuclein.
At the La Jolla Institute of Immunology, researchers have shown that small portions of misfolded alpha-synuclein in a mouse model can appear on the outside of neurons in the gut, which makes the neurons vulnerable to attack from the immune system. This immune attack on neurons in the gut may produce symptoms of constipation and other gastrointestinal effects resembling those seen in Parkinson’s patients years before they are diagnosed with the disease.
Post-mortem studies have shown that the immune response in Parkinson’s takes the form of microglial activation and immunoglobulin deposition within the brain along with sustained neuroinflammation in the periphery, with changes in cells of the innate immune system (particularly monocytes), as well as effects on adaptive immunity, such as T-cell activation. Abnormal alpha-synuclein can also trigger pro-inflammatory cytokines and chemokines, found to be elevated in blood and cerebrospinal fluid in patients with Parkinson’s.
A longitudinal study of newly diagnosed Parkinson’s patients conducted at the University of Alabama at Birmingham was consistent with post-mortem findings. Those with Parkinson’s were found to have increased central inflammation, noted via nuclear imaging and measurement of cytokines, compared to healthy control patients.18 F-DPA-714 is a PET radioligand that binds with high affinity to a translocator-protein (TSPO), mainly expressed on activated microglia, with increased binding noted in de novo Parkinson’s patients. Parkinson’s disease subjects show higher 18F-DPA-714 binding protein in the putamen, thalamus, substantia nigra, and cortical brain regions. Patients with Parkinson’s were also found to have elevated MDC/CCL2—chemokines produced by microglia that serve as an attractant for monocytes and T-cells.
Studies have also shown elevated TSPO binding in the substantia nigra and occipital cortex of patients with REM sleep behavior disorder, along with changes in peripheral immune cell populations and plasma cytokines, indicating that immune system activation occurs even before the motor stages of Parkinson’s. Several studies have shown that pro-inflammatory cytokines including TNF-α, interleukin [IL]-1β, IL-6, and interferon [IFN]γ, as well as circulating T cells—which recognize specific alpha-synuclein-derived neo-epitopes—are abundant in the first decade after diagnosis and likely during the prodromal phase. Thus, the immune system, and reactivity to alpha-synuclein, is implicated in prodromal and early stages of Parkinson’s.
In our next article, we will focus on infectious, toxic, and genetic factors that might trigger these neuroinflammatory and subsequent neurodegenerative processes that lead to Parkinson’s disease and related conditions.
References:
Garretti F, Monahan C, Sloan N, et al. Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease.
Neuron. 2023;S0896-6273(23)00548-2. doi:10.1016/j.neuron.2023.07.015
Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease.
Nat Rev Immunol. 2022;22(11):657-673. doi:10.1038/s41577-022-00684-6
Yacoubian TA, Fang YD, Gerstenecker A, et al. Brain and systemic inflammation in de novo Parkinson’s disease.
Mov Disord. 2023;38(5):743-754. doi:10.1002/mds.29363
