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Parkinson's Disease involves toxic alpha-synuclein (α-syn) aggregates. This study reveals perforated endolysosomes in neurons, facilitating α-syn aggregation and neuronal death, offering a potential therapeutic target.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Pathology

Background:

  • Endocytosis internalizes cellular components and can introduce pathological aggregates like alpha-synuclein (α-syn).
  • Parkinson's Disease (PD) is characterized by the aggregation of α-syn.
  • The precise mechanisms initiating α-syn aggregation within neurons remain under investigation.

Purpose of the Study:

  • To investigate the role of endolysosomes in the genesis of toxic α-syn aggregates.
  • To explore the potential involvement of endolysosomal structural abnormalities in PD pathogenesis.
  • To identify therapeutic strategies targeting endolysosomal integrity to prevent α-syn aggregation.

Main Methods:

  • Utilized human induced pluripotent stem cell-derived neurons (iNs) and CA1 pyramidal neurons.
  • Employed live-cell imaging to observe endolysosome dynamics and perforations.
  • Applied 3D electron microscopy to identify structural features of endolysosomes.
  • Investigated the effect of PIKfyve inhibition on α-syn aggregation and neuronal survival.

Main Results:

  • Discovered intrinsically perforated endolysosomes in approximately 5% of neurons, a feature absent in non-neuronal cells.
  • Demonstrated that internalized α-syn preformed fibrils (PFFs) seeded aggregation of endogenous α-syn within late endosomes and lysosomes of iNs.
  • Observed that this aggregation led to neuronal death, while non-neuronal cells remained unaffected.
  • Showed that inhibiting PIKfyve reduced α-syn aggregation and associated neuronal death.

Conclusions:

  • Neuron-specific endolysosomal perforations may facilitate cytosolic access of α-syn to internalized PFFs, initiating toxic aggregation.
  • Maintaining endolysosomal integrity emerges as a potential therapeutic strategy for synucleinopathies like Parkinson's Disease.