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Updated: Jun 3, 2025

Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils

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Biological Amyloids Chemically Damage DNA.

Istvan Horvath1, Obed Akwasi Aning1, Sriram Kk1

  • 1Department of Life Sciences, Chalmers University of Technology, 412 96 Gothenburg, Sweden.

ACS Chemical Neuroscience
|January 9, 2025
PubMed
Summary
This summary is machine-generated.

Alpha-synuclein (αS) fibrils interact with and damage DNA, causing strand breaks. This amyloid-induced DNA damage may contribute to the development of Parkinson's disease (PD).

Keywords:
DNA damageParkinson’s diseasealpha-synucleinamyloidscatalytic activitynanochannels

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Biological amyloids, protein polymers with a cross-β structure, were previously thought to be chemically inert.
  • Recent studies have shown that some amyloids can catalyze chemical reactions in vitro.
  • The functional capabilities of amyloids are still being explored.

Purpose of the Study:

  • To investigate the chemical reactivity of α-synuclein (αS) amyloid fibrils toward DNA.
  • To determine if αS amyloids can induce DNA damage.
  • To explore the potential role of αS amyloid-DNA interactions in Parkinson's disease (PD).

Main Methods:

  • In vitro binding assays to quantify αS amyloid-DNA interactions.
  • Assays using DNA repair enzyme activity as a proxy for DNA damage.
  • Nanochannel analysis of long DNA molecules to detect double-strand breaks.
  • Yeast cell model to assess DNA damage upon αS overexpression.

Main Results:

  • αS amyloids bind to DNA at micromolar concentrations in vitro.
  • DNA-amyloid interactions lead to chemical modifications, including single-strand nicks.
  • Double-strand DNA breaks are observed.
  • The amyloid structure of αS is crucial for DNA modification; monomers do not cause damage.
  • αS overexpression increases DNA damage in a yeast model.

Conclusions:

  • αS amyloid fibrils chemically perturb DNA, adding to the known reactivity of biological amyloids.
  • The amyloid fold of αS is essential for its DNA-damaging activity.
  • Given that αS amyloids are found in Parkinson's disease patient neurons and DNA damage is a PD hallmark, αS amyloids may contribute to PD pathogenesis through direct DNA damage.