NeuralCipher Research overview
The text below is the source article’s original abstract under a verified reuse license. cc by
Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson's disease, the molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model to specifically immunoisolate neuronal lysosomes, and established a long-term culture model where αSyn aggregates are produced within neurons without the addition of exogenous fibrils. We show that neuronally generated pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis. The released aggregates are non-membrane enveloped and seeding-competent. Additionally, we find that this release is dependent on neuronal activity and cytosolic Ca2+. These results propose lysosomal exocytosis as a central mechanism for the release of aggregated and degradation-resistant proteins from neurons.
Scientific assessment
Research question
Assess the question within the original study’s scope.
Methods & sample
Check the source article for study design and sample details.
Key findings
An editorially approved findings summary is not yet published for this record.
Limitations
Generalizability, bias and clinical meaning require separate assessment.
Methods, samples and clinical conclusions are not inferred from bibliographic metadata.