Dataset Information

Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles

ABSTRACT: α-synuclein (α-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinson’s disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between α-syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined SH-SY5Y cells exposed to α-syn fibrils vs control cells with a focus on mitochondria. We found that upon exposure to α-syn fibrils, mitochondria cristae structure gets defects, and mitochondria enhance the budding of mitochondrial-derived vesicles (MDVs). MDV formation reflects an evolutionarily conserved mechanism reminiscent of bacterial outer membrane vesicle biogenesis. Structural proteomics analysis by mass spectrometry corroborates this microscopy observation by identifying changes in multiple proteins that regulate cristae structure, MDV formation, and trafficking. Our results suggest that α-syn may promote MDV generation, and support an important link between α-syn and mitochondria which will be important for future mechanistic studies. The processes we detected could be of interest for diagnostics and potential therapeutic interventions.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tetiana Serdiuk

LAB HEAD: Thomas Braun

PROVIDER: PXD078690 | Pride | 2026-06-29

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	201205_EX1_tserdiukExp_004a_library_35.raw	Raw
	201205_EX1_tserdiukExp_004a_library_36.raw	Raw
	201205_EX1_tserdiuk_Exp_004a_001.raw	Raw
	201205_EX1_tserdiuk_Exp_004a_002.raw	Raw
	201205_EX1_tserdiuk_Exp_004a_003.raw	Raw

Items per page:

1 - 5 of 17

Publications

Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles.

Braun Thomas T Reber Viviane V Tiberi Cinzia C Fränkl Andri A Ghosh Dhiman D Riek Roland R Serdiuk Tetiana T

Proceedings of the National Academy of Sciences of the United States of America 20260608 24

α-synuclein (α-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinson's disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between α-syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined SH-SY5Y cells exposed to α-syn fibrils vs control cells with a focu ...[more]

PMID: 42258734

Similar Datasets

Project description:Parkinson’s disease (PD) is driven by the prion-like propagation of α-synuclein (α-syn) fibrils, but the molecular and structural mechanisms governing their neuronal uptake, intracellular trafficking, and mitochondrial engagement remain incompletely defined. Here, we integrated two core cutting-edge approaches—time-resolved proximity labeling (PL) proteomics and cryogenic electron tomography (cryo-ET)—along with functional analyses to resolve these critical processes. To dissect the dynamic protein interactions that mediate α-syn fibrils neuronal uptake and trafficking, we developed a novel Rose Bengal-conjugated α-syn fibrils (RB-PFFs) proximity labeling strategy, a powerful tool that enabled the capture of stage-specific interactomes throughout α-syn fibrils intracellular transit. A key insight from this time-resolved proximity proteomics approach was the progressive enrichment of mitochondrial proteins, which directly guided our subsequent investigation of α-syn fibrils-mitochondrial interactions. Complementing these proteomic analyses, cryo-ET—validated by correlative light and electron microscopy (CLEM)—provided definitive near-atomic resolution visualization of α-syn fibrils interacting with receptor-rich densities on the axonal plasma membrane prior to internalization, being sequestered within lysosomal compartments following intracellular trafficking, and subsequently escaping lysosomes to make direct contact with the outer mitochondrial membrane (OMM) in naive neurons, resolving the structural basis of this critical pathogenic interaction. Functional analyses further confirmed that α-syn fibrils engagement with mitochondria induces mitochondrial DNA (mtDNA) release, with Voltage-Dependent Anion Channel 1 (VDAC1) implicated as a mediator of this process. Together, our findings, anchored in proximity proteomics and cryo-ET, establish a comprehensive molecular and structural framework for α-syn fibrils neuronal uptake and mitochondrial engagement, identifying potential therapeutic targets for mitigating α-syn-related pathogenesis in PD.