Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs

  • J Cell Biol. 2025 Feb 3;224(2):e202401136. doi: 10.1083/jcb.202401136.
Anwesha Sanyal  1  2 ,  Gustavo Scanavachi  1  2 ,  Elliott Somerville  2 ,  Anand Saminathan  1  2 ,  Athul Nair  2 ,  Ricardo F Bango Da Cunha Correia  1  2 ,  Beren Aylan  1  2 ,  Ewa Sitarska  1  2 ,  Athanasios Oikonomou  3 ,  Nikos S Hatzakis  3 ,  Tom Kirchhausen  1  2  4
Affiliations
  • 1. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 2. Program in Cellular and Molecular Medicine, Boston Children's Hospital , Boston, MA, USA.
  • 3. Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
  • 4. Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
PMID: 39714357 DOI: 10.1083/jcb.202401136
Abstract

Endocytosis, required for the uptake of receptors and their ligands, can also introduce pathological aggregates such as α-synuclein (α-syn) in Parkinson's Disease. We show here the unexpected presence of intrinsically perforated endolysosomes in neurons, suggesting involvement in the genesis of toxic α-syn aggregates induced by internalized preformed fibrils (PFFs). Aggregation of endogenous α-syn in late endosomes and lysosomes of human iPSC-derived neurons (iNs), seeded by internalized α-syn PFFs, caused the death of the iNs but not of the parental iPSCs and non-neuronal cells. Live-cell imaging of iNs showed constitutive perforations in ∼5% of their endolysosomes. These perforations, identified by 3D electron microscopy in iNs and CA1 pyramidal neurons and absent in non-neuronal cells, may facilitate cytosolic access of endogenous α-syn to PFFs in the lumen of endolysosomes, triggering aggregation. Inhibiting the PIKfyve phosphoinositol kinase reduced α-syn aggregation and associated iN death, even with ongoing PFF endolysosomal entry, suggesting that maintaining endolysosomal integrity might afford a therapeutic strategy to counteract synucleinopathies.

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