Inflammation and α-synuclein's prion-like behavior in Parkinson's disease--is there a link?

Abstract

Parkinson's disease patients exhibit progressive spreading of aggregated α-synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of α-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded α-synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of α-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of α-synuclein and that novel anti-inflammatory therapies targeting this mechanism could slow disease progression.

Fig. 1

Possible initiation mechanism and spreading of synucleinopathy from the olfactory bulb to the brain. Pathogens or particles entering the olfactory epithelium spread to the olfactory bulb (OB) through axons of olfactory neurons. The pathogens induce an inflammatory response and oxidative stress in the OB and damage that accumulates overtime and induces α-syn misfolding and aggregation. α-Syn then transfers to interconnected regions via prion-like mechanisms and reaches the midbrain. General inflammation could promote α-syn accumulation and spread

Fig. 2

Possible spreading of synucleinopathy from the enteric nervous system to the brain. Macrophages in the lamina propria become reactive upon natural (e.g., bacteria, viruses, etc.) or induced (toxins) immune challenges. These cells react with secretion of inflammatory mediators (cytokines, chemokines, ROS, etc.), which can harm the surrounding tissue and may induce accumulation of α-syn in enteric nerves. This could alter gut activity, which early on may be observable by abnormal intestinal motility and constipation. Aggregated α-syn may be released by damaged nerve cells, which may further activate local macrophages. Cell-to-cell transmission could further contribute to the progression of synucleinopathy, which would eventually propagate from the enteric nervous system into the SNpc via nuclei in vagus and spinal cord

Fig. 3

α-Syn propagates from mouse brain to a graft of dopaminergic neurons. Confocal planes of a tyrosine hydroxylase-positive mouse neuron (green, a) transplanted in the striatum of a mouse overexpressing human α-syn. The arrowheads indicate the localization inside the grafted mouse cell of several human α-syn (red, b) dots, which have been transferred from the host brain. c An overlay of a and b. Scale bar 5 μm. Figure courtesy of Dr. Elodie Angot