New mechanism found to drive α-synuclein spread in Parkinson's disease and related disorders

Parkinson's disease (PD) and Lewy body dementia (LBD) are incurable and progressive neurodegenerative disorders, with some overlapping symptoms. An estimated 10 million people worldwide live with PD, while the figure for LBD—the second most common form of dementia after Alzheimer's—is unclear. Both diseases involve Lewy bodies—abnormal clumps of α-synuclein protein in brain cells.

Previous research on Lewy bodies have often focused on the rigid core of these fibrils. Now, however, a study by HE Zhuohao's team from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences, along with collaborators, has revealed the critical role of the "fuzzy coat" of α-synuclein—the flexible, disordered regions that extend from the fibril core—in prion-like pathological transmission in synucleinopathies. Their work was published in Neuron on April 10.   

The researchers first conducted serial amplification experiments to mimic the in vivo process of pathological protein transmission, identifying two structural variants, or polymorphs, of these fibrils: Mini-P, with a more compact fuzzy coat, and Mini-S, with a looser, more extended fuzzy coat.

Using a combination of advanced structural biology techniques—including cryo-electron microscopy, solid-state nuclear magnetic resonance, and hydrogen/deuterium exchange mass spectrometry—the researchers found that the two polymorphs are distinguished by the dynamic nature of their fuzzy coats, even though their rigid cores are remarkably similar. 

They also discovered that Mini-P fibrils exhibited greater neuronal seeding activity—i.e., transmission—compared to Mini-S, in part because the compact arrangement of Mini-P effectively shields some of the negative charges on the fuzzy coat. This shielding minimizes repulsion by neuronal receptors, particularly heparan sulfate proteoglycan (HSPG), thereby promoting more efficient neuronal uptake and increased resistance to proteolysis.

This research provides critical insight into the molecular mechanisms underlying the spread of pathological proteins between neurons—a process thought to exacerbate disease progression. As α-synuclein fibrils propagate from cell to cell, even subtle differences in fibril structure can dramatically alter their ability to seed new pathological aggregates. 

Additionally, the findings identify the fuzzy coat as a potential therapeutic target. Rather than attempting to eliminate all pathological protein aggregates—a task that is both energy-intensive and challenging—a more promising strategy might involve specifically targeting the fuzzy coat. By altering its structure or disrupting its interaction with the fibril core, it may be possible to reduce the efficiency of fibril transmission, slowing disease progression.

In addition, the researchers validated their model using conformation-specific antibodies, which could distinguish between Mini-P-like (seeding competent) and Mini-S-like (seeding incompetent) pathological protein in human brain tissues from patients with synucleinopathies. This suggests that the mechanisms observed in vitro are relevant to human disease. 

This study marks a significant shift in the field of neurodegenerative disease research. It underscores the importance of looking beyond the well-studied rigid fibril core to understand the complex biology of protein aggregation. The study not only deepens our understanding of neurodegenerative disease pathology but also paves the way for the development of more targeted interventions.