Pathological alpha-synuclein propagates through neural networks.

Area of Science:

• Neuroscience
• Pathology
• Biochemistry

Background:

• Alpha-synuclein (αS) aggregates form hallmark inclusions in Parkinson's disease and related α-synucleinopathies.
• Previous research demonstrated prion-like propagation of αS pathology after intracerebral fibril injection in mice.
• The precise mechanisms and anatomical spread of αS pathology remain incompletely understood.

Purpose of the Study:

• To elucidate the anatomical sites and mechanisms of α-synuclein pathology propagation in the brain.
• To investigate the potential for αS pathology to influence other protein aggregation pathways.

Main Methods:

• Recombinant mouse α-synuclein fibrils were stereotactically injected into the substantia nigra, striatum, or entorhinal cortex of wild-type mice.
• Pathology distribution was assessed at one month post-injection.
• Immunohistochemistry was used to detect α-synuclein, phosphorylated tau, and TDP-43.
• Sarkosyl-insoluble fractions from injected mice were used to induce pathology in naive mice.

Main Results:

• Distinct patterns of α-synuclein pathology spread were observed depending on the injection site, reaching distant connected neurons within one month.
• Intriguingly, phosphorylated tau and TDP-43 pathologies were detected in mice injected with α-synuclein fibrils, suggesting a synergistic effect on aggregation.
• These tau and TDP-43 inclusions were rarely co-localized with α-synuclein pathology.
• Intracerebral injection of aggregated αS from affected wild-type mice induced pathology in naive wild-type mice.

Conclusions:

• Alpha-synuclein aggregation propagates through neural networks via prion-like mechanisms.
• Alpha-synuclein accumulation may synergistically promote the aggregation of tau and TDP-43 proteins.