Parkinson’s disease (PD) is a progressive neurodegenerative disease associated with the death of dopaminergic neurons in the substantia nigra of the brain and the presence of protein inclusions called Lewy bodies. The main component of Lewy bodies is alpha-synuclein. Manifestations of PD are resting tremors, stiffness of the muscles of the neck, trunk and limbs, impaired coordination and postural instability.
However, the manifestations of Parkinson’s disease are not limited to movement disorders. Preclinical occurrences of PD are sleep disturbances and gastrointestinal tract disorders. Moreover, these symptoms can occur several decades earlier than movement disorders.
The cause of early symptoms of Parkinson’s disease is neuroinflammation and immune dysfunction. The immune system is involved in the development of Parkinson’s disease, confirming the association of PD with other autoimmune and inflammatory diseases, including Crohn’s disease. In addition, the HLA-DRA gene mutation associated with the risk of PD enhances the immune system’s inflammatory response to environmental factors such as insecticides. For carriers of this mutation, insecticides increase the risk of Parkinson’s disease by a factor of 2.5.
Inflammation Influence in The Pathogenesis and Progression of Parkinson’s Disease
A significant risk factor for many neurodegenerative diseases is age. The aging of the immune system contributes to neurodegeneration.
The main signs of aging of the immune system are age-related immunodeficiency and inflammation. Inflammation is manifested by chronically elevated levels of cytokines such as C-reactive protein (CRP), IL-6, and tumor necrosis factor (TNF). The production of cytokines is stimulated by cells of innate and acquired immunity.
The functioning of the immune system can be disrupted with age. It is also disrupted in Parkinson’s disease.
Role of The Immune System in Parkinson’s Disease: T Cells
Several studies have shown that T cells enter the brains of Parkinson’s patients, promoting inflammation and neuronal death. In the compact part of the substantia nigra of the brain of patients with Parkinson’s disease, T-killers and T-helpers were present at higher levels than in healthy people. At the same time, the level of T-helpers in the blood was reduced in patients with PD.
In PD, the activity of regulatory T cells is increased. Interestingly, Parkinson’s patients are dopamine deficient, and dopamine reduces the function of regulatory T cells. Moreover, dopaminergic drugs may not change the activity of T-cells, which was confirmed by studies comparing patients with PD who received dopamine replacement therapy with patients who did not.
Dopamine receptors on immune cells contribute to the progression of Parkinson’s disease. The expression of dopamine T-cell receptors correlates with the severity of PD.
Some T cells from preclinical PD patients overreact to alpha-synuclein. The most substantial response of T-cells is immediately after the appearance of the first movement disorders. Later the response declines. Monitoring the response of T cells to alpha-synuclein may allow early detection of Parkinson’s disease in risk groups.
Interferon-Gamma Contributes to The Progression of Parkinson’s Disease
Immune cell dysregulation can cause increased production of inflammatory cytokines that contribute to neuronal death in Parkinson’s disease. T cells are the primary producers of interferon-gamma (IFN-gamma). Patients with Parkinson’s disease have increased levels of T cells producing the pro-inflammatory cytokine interferon-gamma and decreased levels of T cells producing the anti-inflammatory cytokine IL-4.
The levels of pro-inflammatory cytokines TNF, IFN-gamma, IL-1β, IL-6, IL-2, CXCL8, and CCL2 are elevated in the brain and serum of patients with PD. The higher the level of these cytokines, the more severe the PD and the greater the risk of disability.
IFN-gamma causes the death of dopaminergic neurons and degeneration of the nigrostriatal pathway, which is responsible for purposeful movement. In the midbrain of patients with PD, higher levels of IFN-gamma are observed, along with a significant alpha-synuclein expression.
Pathogenetic mechanisms may be familiar to some chronic inflammatory diseases, infections, and Parkinson’s disease. LRRK2 is the target gene for interferon-gamma. LRRK2 expression is upregulated during inflammation. Mutations in the LRRK2 gene are associated with Parkinson’s disease, Crohn’s disease, and leprosy.
Parkinson’s Disease Starts in The Gut
Gastrointestinal disorders, including constipation, occur several decades before movement disorders in PD. Gut dysbiosis is associated with an inflammatory environment that may contribute to Parkinson’s disease.
The composition of the intestinal microbiota in patients with PD differs from the composition of the microbiota of healthy ones. Changes in microbiota composition are associated with gut inflammation in PD. Thus, Bacteroides and Verrucomicrobia levels correlate with plasma levels of TNF and IFN-gamma, respectively.
Higher levels of inflammatory mediators were found in the stool of PD patients compared to healthy controls. Some of these mediators may contribute to the progression of Parkinson’s disease.
Conclusion
Parkinson’s disease starts in the gut and then spreads to the brain. Diagnosing PD before the onset of movement disorders, including monitoring the T-cell response to alpha-synuclein, will help prevent, delay, or halt the progression of Parkinson’s disease.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
Reference
Inflammation and immune dysfunction in Parkinson disease
