Increased Accumulation of α-Synuclein in Inflamed Appendices of Parkinson's Disease Patients

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Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

It is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues. In the brain, alpha-synuclein is found mainly at the tips of neurons in specialized structures called presynaptic terminals.

The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (Parkinson's disease) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of Parkinson's disease.

In 2007, Braak and co-authors advanced a ‘dual-hit hypothesis’ about the pathogenesis of idiopathic Parkinson's disease, according to which an unknown pathogen akin to a slow-virus may enter the nervous system through both the nasal and intestinal mucosae, eventually resulting in a cascade of neurodegenerative events in the brain. enter image description here

In 2018 Killinger, Labrie and colleagues reported that in two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, they observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset.

After studying 48 subjects without Parkinson disease, they also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology–associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD.

In this new study by Yuhua Chen, Feng Yu and colleagues in University of Science and Technology of China in Hefei, investigated appendix abnormality in patients with Parkinson's disease.

The scientists assessed appendix morphology in 100 patients with Parkinson's disease and 50 control subjects by multislice spiral computed tomography. They analyzed the clinical characteristics of patients with Parkinson's disease with diseased appendices, which was confirmed in seven patients by histopathological analysis.

Chronic appendicitis-like lesions were detected in 53% of patients with Parkinson's disease, but these were not associated with the duration of motor symptoms.

Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder are known risk factors for Parkinson's disease.

The seven patients with Parkinson's disease who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation.

These results indicate an association between chronic appendicitis-like lesions and Parkinson's disease, and suggest that α-Syn accumulation in the diseased appendix occurs in Parkinson's disease. The appendix may play a role in the pathogenesis of Parkinson's disease, but the exact mechanism remains unclear. The appendix could be a source of pathological α-syn that propagates to the central nervous system, but a “second-hit” may be required for this phenomenon to occur. Factors like chronic inflammation, microbiome perturbations, formation of α-syn truncation products, and impaired cellular clearance of α-syn aggregates may serve to promote the generation and spread of pathology from the appendix to the brain. The vagus nerve, compromised BBB integrity, and/or age-dependent degeneration of the CNS lymphatic system may be routes by which α-syn seeds accumulate in the brain.

Alternatively (or in addition), immunosurveillance functions of the appendix may contribute to acquiring autoimmunity towards α-syn, including the generation of self-reactive T cells and autoantibodies. Hence, studying the accumulation and possible spreading of α-syn from appendix to brain could help our understanding of the origins of Parkinson's disease.

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