Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs.
Anwesha Sanyal1,2, Gustavo Scanavachi1,2, Elliott Somerville2
1Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
The Journal of Cell Biology
|December 23, 2024
Summary
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.
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.
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