Rise-and-fall dynamics reveal a molecular and cellular vulnerability axis in prion-like α-synuclein propagation.

Area of Science:

• Neuroscience
• Pathology
• Systems Biology

Background:

• Misfolded protein spread is key to neurodegenerative diseases like Parkinson's.
• Current understanding of protein spread dynamics is limited by sparse data.
• Temporal evolution of pathology is crucial but often unexamined.

Purpose of the Study:

• To investigate the temporal dynamics of alpha-synuclein pathology spread.
• To model the network-based progression of pathology in a Parkinson's disease mouse model.
• To identify factors contributing to regional vulnerability in neurodegeneration.

Main Methods:

• Longitudinal histopathology measurements of alpha-synuclein in a Parkinson's disease mouse model.
• Network-based dynamical modeling of pathology spread across hundreds of brain regions.
• Analysis of transcriptomic and cellular composition data to identify vulnerability factors.

Main Results:

• Regional pathology exhibits rise-and-fall trajectories, not just accumulation.
• A one-dimensional vulnerability axis was identified, correlating with specific brain regions.
• This axis is characterized by monoaminergic neuronal composition and proteostatic/metabolic gene expression.
• The identified vulnerability axis and its transcriptomic structure were validated in an independent dataset.

Conclusions:

• Regional vulnerability in neurodegeneration is governed by low-dimensional dynamics.
• Pathology progression is characterized by complex rise-and-fall patterns.
• Molecular and cellular features define a conserved vulnerability axis in Parkinson's disease models.