Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.

TitleLysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.
Publication TypeJournal Article
Year of Publication2022
AuthorsXie YXue, Naseri NN, Fels J, Kharel P, Na Y, Lane D, Burré J, Sharma M
JournalNat Commun
Volume13
Issue1
Pagination4918
Date Published2022 Aug 22
ISSN2041-1723
Keywordsalpha-Synuclein, Animals, Exocytosis, Lysosomes, Mice, Neurons, Synucleinopathies
Abstract

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.

DOI10.1038/s41467-022-32625-1
Alternate JournalNat Commun
PubMed ID35995799
PubMed Central IDPMC9395532
Grant List1R01AG052505 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
RF1 NS126342 / NS / NINDS NIH HHS / United States
1R01NS121077 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
R01 NS102181 / NS / NINDS NIH HHS / United States
New Investigator in Alzheimer's Research Grant / / American Federation for Aging Research (American Federation for Aging Research, Inc.) /
R01 NS121077 / NS / NINDS NIH HHS / United States
R01 NS113960 / NS / NINDS NIH HHS / United States
R01 AG052505 / AG / NIA NIH HHS / United States
F31 NS098623 / NS / NINDS NIH HHS / United States
1R01NS102181 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
NIRG-15-363678 / ALZ / Alzheimer's Association / United States
F31NS098623 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
1R01NS113960 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
RF1NS126342 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
1R01NS095988 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
R01 NS095988 / NS / NINDS NIH HHS / United States