Pathological Link Between Kidney Disease and Parkinson’s Disease

Academic Background

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein (α-syn) in the brain, forming Lewy bodies (LBs) and Lewy neurites (LNs). In recent years, increasing evidence suggests that the pathological aggregation of α-syn may originate in peripheral organs and spread to the central nervous system (CNS) in a prion-like manner. Although studies have shown a significantly increased incidence of PD in patients with chronic renal failure (CKD), the specific mechanisms linking the two remain unclear. Therefore, this study aims to explore the role of the kidney in the propagation of α-syn pathology and reveal the potential connection between kidney disease and PD.

Source of the Paper

This paper was co-authored by Xin Yuan, Shuke Nie, Yingxu Yang, and others from Renmin Hospital of Wuhan University, Tongji Medical College of Huazhong University of Science and Technology, and other institutions. It was published in Nature Neuroscience in 2024. The research team systematically investigated the critical role of the kidney in the propagation of α-syn pathology through clinical sample analysis, animal experiments, and molecular biology techniques.

Research Process and Results

1. Clinical Sample Analysis

The research team first conducted immunohistochemical analysis on kidney samples from 11 patients with PD or dementia with Lewy bodies (DLB). They found phosphorylated α-syn (pα-syn) deposits in the kidneys of 10 patients, particularly in nerve fibers adjacent to small blood vessels. Additionally, the study was extended to 20 CKD patients, revealing α-syn pathological deposits in the kidneys of 17 patients, despite no history of PD. These results suggest that α-syn pathological deposits may be prevalent in the kidneys of CKD patients and could serve as early pathological markers of PD.

2. Animal Model Construction and Experiments

To further validate the role of the kidney in the propagation of α-syn pathology, the research team constructed various mouse models. First, they observed the distribution of α-syn in the kidneys and brains of healthy and renal failure (RF) mice following intravenous injection of α-syn monomers or preformed fibrils (PFFs). The results showed that α-syn was rapidly cleared in healthy mice but significantly reduced in RF mice, leading to increased deposition in the kidneys and subsequent spread to the brain.

3. Intrarenal Injection of α-syn Fibrils

The research team also directly observed the propagation of α-syn pathology from the kidney to the brain through intrarenal injection of α-syn PFFs. The results showed significant increases in α-syn pathology in the kidneys, spinal cord, and multiple brain regions (including the midbrain, amygdala, hippocampus, and striatum) three months after injection. Notably, blocking the neural connection between the kidney and brain through renal denervation significantly reduced the propagation of α-syn pathology in the brain. This indicates that the kidney propagates α-syn pathology to the brain via neural pathways.

4. Role of Erythrocytic α-syn

The study also found that red blood cells (RBCs) are the primary source of α-syn in the blood, with its concentration in RBCs far exceeding that in cerebrospinal fluid. Through bone marrow transplantation experiments, the research team discovered that transplanting bone marrow from α-syn knockout (snca−/−) mice into α-syn A53T transgenic mice significantly reduced α-syn pathology in the CNS. This suggests that erythrocytic α-syn plays a crucial role in the progression of PD pathology.

Conclusions and Significance

This study is the first to reveal the kidney as a starting point for the propagation of α-syn pathology, which spreads to the brain via neural pathways, leading to the onset of PD. This discovery not only provides a new perspective for understanding the pathological mechanisms of PD but also offers a theoretical basis for developing therapeutic strategies targeting peripheral α-syn. By blocking α-syn deposition in the kidneys or clearing α-syn from the blood, new approaches for the prevention and treatment of PD may emerge.

Research Highlights

1. Kidney as the Starting Point for α-syn Pathology Propagation: This study is the first to identify the critical role of the kidney in the propagation of α-syn pathology, revealing the potential link between kidney disease and PD.
2. Neural Pathway-Mediated Pathology Propagation: Through renal denervation experiments, the research team confirmed the mechanism by which the kidney propagates α-syn pathology to the brain via neural pathways.
3. Key Role of Erythrocytic α-syn: The study found that RBCs are the primary source of α-syn in the blood, and bone marrow transplantation experiments validated the importance of erythrocytic α-syn in the progression of PD pathology.

Other Valuable Information

This study also developed several novel experimental methods, such as intrarenal injection of α-syn PFFs and renal denervation techniques, providing important tools for future related research. Additionally, the research team comprehensively analyzed α-syn pathological deposits using various molecular biology techniques (e.g., immunohistochemistry, Western blotting, ELISA), offering rich data support for understanding the pathological mechanisms of α-syn.

This study not only reveals the critical role of the kidney in the propagation of PD pathology but also provides new insights for developing therapeutic strategies targeting peripheral α-syn, holding significant scientific and practical value.