Progression of phosphorylated α-synuclein in Macaca fuscata

Area of Science:

• Neuroscience
• Pathology
• Biochemistry

Background:

• Prion-like spreading of abnormal proteins, including alpha-synuclein (α-syn), is implicated in neurodegenerative diseases like Parkinson's disease (PD) and dementia with Lewy bodies (DLB).
• Previous studies demonstrated α-syn transmission in animal models, but its propagation in nonhuman primates, which share greater physiological similarity to humans, remained incompletely understood.
• Investigating α-syn propagation in nonhuman primates is crucial for understanding disease mechanisms and developing therapeutic strategies for synucleinopathies.

Discussion:

• Synthetic human α-syn fibrils injected into the macaque striatum induced Lewy bodies and neuronal intracytoplasmic inclusions (NCIs) positive for phosphorylated α-syn, ubiquitin, and p62.
• Pathology spread from the injection site via projection, association, and commissural fibers to the putamen, substantia nigra, and frontal cortex.
• While α-syn pathology was widespread, neuronal loss and gliosis were generally mild, suggesting a slow or limited progression despite initial fibril injection.

Key Insights:

• This study provides evidence of α-syn propagation in a macaque model, mirroring prion-like mechanisms observed in human synucleinopathies.
• The findings demonstrate that synthetic α-syn fibrils can induce pathological changes and spread through neural networks in primates.
• The observed limited neurodegeneration suggests that α-syn pathology may precede significant neuronal loss, offering a window for intervention.

Outlook:

• Further research should explore the long-term consequences of α-syn propagation and the factors influencing its progression rate in primates.
• This model can be utilized to test the efficacy of potential therapeutics targeting α-syn aggregation and transmission.
• Investigating the transmission routes and mechanisms in greater detail will refine our understanding of synucleinopathies.