Toxic Metamorphosis—How Changes from Lysosomal to Cytosolic pH Modify the Alpha-Synuclein Aggregation Pattern

Bisher Eymsh, Alice Drobny, Timon R. Heyn, Wei Xiang, Ralph Lucius, Karin Schwarz, J.K. Keppler, Friederike Zunke*, Philipp Arnold*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Alpha-synuclein (aSyn) is a cytosolic, aggregation-prone protein that is associated with neurodegenerative disorders like Parkinson’s disease. Interestingly, the protein can appear in different conformations, including monomeric and oligomeric forms as well as amyloid fibrils. Its individual structural constituents seem to be dependent on various factors and the composition of the respective cellular surroundings. Although under physiological conditions, most aSyn is found in the cytosol and synapses of neurons, aSyn can also be found in lysosomal compartments, where it gets degraded. We here compare the assembly speed, morphology, folding state, and spreading of aSyn at cytosolic pH (pH 7.4) and lysosomal pH (pH 5) using Thioflavin T, transmission electron microscopy, circular dichroism, and Fourier transform infrared spectroscopy. Interestingly, we found substantial differences between aSyn aggregation under neutral and acidic pH conditions, like those present in cytosolic and lysosomal cellular compartments. Also, lysosomal aSyn enriched from an aSyn-overexpressing cell line was able to seed aggregation in a concentration-dependent manner. Moreover, we observed that aSyn aggregates formed under in vitro lysosomal pH (pH 5) conditions were not stable at neutral pH and collapsed into partly soluble aggregates with changed structural characteristics. Our findings have meaningful implications in intracellular toxicity events as well as in lysis procedures for molecular and structural characterization of intracellular aSyn conformers.
Original languageEnglish
Pages (from-to)4673-4684
JournalBiomacromolecules
Volume21
Issue number12
DOIs
Publication statusPublished - 28 Sep 2020

Keywords

  • Nanofibers
  • Peptides and proteins
  • Monomers
  • Aggregation
  • Transmission electron microscopy

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