# A Pathophysiological Model of Parkinson’s Disease Based on Microvascular Flow Disturbance and Leukocyte-Mediated Oxidative Injury in Critical Pigmented Neuronal Niches

## TL;DR

This paper proposes a new model for Parkinson’s disease, linking it to blood flow issues and immune cell activity in specific brain regions with pigmented neurons.

## Contribution

The novel hypothesis connects microvascular flow disturbance and immune-mediated oxidative injury to the onset of Parkinson’s disease pathology.

## Key findings

- Blood flow disturbance in pigmented neuronal niches may trigger immune cell activation and oxidative injury.
- Oxidative stress from immune cells could lead to accumulation of neuromelanin, lipofuscin, and alpha-synuclein.
- This mechanism may explain the spread of neurotoxic alpha-synuclein and progressive degeneration in Parkinson’s disease.

## Abstract

The authors hypothesize that idiopathic Parkinson’s disease may result from an alteration in microvascular flow at a “critical point” in the nervous system that is characterized by pigmented cells that express neuromelanin and/or lipofuscin. “Critical points” include the olfactory epithelium/bulb, the autonomic nervous system, the enteric nervous system, the prefrontal–cortico-pontine network, and the amygdala. Hypoxia–ischemia following blood flow disturbance would recruit and activate leukocytes and induce the infiltration of peripheral immune cells into neural tissue. The excess of toxic factors produced by hyperactive immune cells, such as myeloperoxidase and its derivatives, would cause the oxidation of lipids, proteins, and biogenic monoamines such as dopamine, which in turn would facilitate the accumulation and precipitation of neuromelanin, lipofuscin, and alpha-synuclein. In addition, neuromelanin and lipofuscin precipitates may accentuate the misfolding and aggregation of alpha-synuclein. This “amplification” mechanism could help explain the crucial role of pigmented neurons in the onset of Parkinson’s disease pathology, triggering abnormal neurotoxic alpha-synuclein spread throughout the nervous system from the “critical point” of origin, and enabling a self-perpetuating degenerative process. The proposed hypothesis may have implications for the identification of new therapeutic targets, early prevention strategies, and the development of vascular and/or immune biomarkers.