On the Cluster Formation of α-Synuclein Fibrils

Marija Dubackic; Ilaria Idini; Veronica Lattanzi; Yun Liu; Anne Martel; Ann Terry; Michael Haertlein; Juliette M Devos; Andrew Jackson; Emma Sparr; Sara Linse; Ulf Olsson

doi:10.3389/fmolb.2021.768004

On the Cluster Formation of α-Synuclein Fibrils

Front Mol Biosci. 2021 Oct 19:8:768004. doi: 10.3389/fmolb.2021.768004. eCollection 2021.

Authors

Marija Dubackic¹, Ilaria Idini¹, Veronica Lattanzi^{1

2}, Yun Liu^{3

4}, Anne Martel⁵, Ann Terry^{6

7}, Michael Haertlein⁸, Juliette M Devos⁸, Andrew Jackson^{1

9}, Emma Sparr², Sara Linse², Ulf Olsson¹

Affiliations

¹ Division of Physical Chemistry, Department of Chemistry, Lund University, Lund, Sweden.
² Division of Biochemistry and Structural Biology, Department of Chemistry, Lund University, Lund, Sweden.
³ Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD, United States.
⁴ Chemical and Biomolecular Engineering Department, University of Delaware, Newark, DE, United States.
⁵ Institut Laue-Langevin, Grenoble, France.
⁶ ISIS Neutron and Muon Source, Harwell Oxford, Didcot, United Kingdom.
⁷ Max IV Laboratory, Lund University, Lund, Sweden.
⁸ Life Sciences Group, Institut Laue-Langevin, Grenoble, France.
⁹ European Spallation Source, Lund, Sweden.

Abstract

The dense accumulation of α-Synuclein fibrils in neurons is considered to be strongly associated with Parkinson's disease. These intracellular inclusions, called Lewy bodies, also contain significant amounts of lipids. To better understand such accumulations, it should be important to study α-Synuclein fibril formation under conditions where the fibrils lump together, mimicking what is observed in Lewy bodies. In the present study, we have therefore investigated the overall structural arrangements of α-synuclein fibrils, formed under mildly acidic conditions, pH = 5.5, in pure buffer or in the presence of various model membrane systems, by means of small-angle neutron scattering (SANS). At this pH, α-synuclein fibrils are colloidally unstable and aggregate further into dense clusters. SANS intensities show a power law dependence on the scattering vector, q, indicating that the clusters can be described as mass fractal aggregates. The experimentally observed fractal dimension was d = 2.6 ± 0.3. We further show that this fractal dimension can be reproduced using a simple model of rigid-rod clusters. The effect of dominatingly attractive fibril-fibril interactions is discussed within the context of fibril clustering in Lewy body formation.

Keywords: Lewy bodies (LB); alpha-synuclein; amyloid fibril; fractal cluster; rigid-rod cluster modeling; small-angle neutron scattering (SANS).