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Physics: Two publications in Nature Communications
Parkinson’s research: Lipids influence the formation of protein clumps

After Alzheimer’s, Parkinson’s is the world’s most common neurodegenerative disease. Up to 400,000 people in Germany alone suffer from it. In this disease, defective alpha-synuclein proteins form thread-like structures – so-called fibrils, which probably damage nerve cells when they clump together. A research team from the Max PIanck Institute (MPI) for Multidisciplinary Sciences in Göttingen, Heinrich Heine University Düsseldorf (HHU) and Jülich Research Center (Forschungszentrum Jülich – FZJ) has now shown for the first time how lipids bind to the fibril surface and influence the arrangement of the synuclein proteins within the fibrils. As the team demonstrated, the drug candidate anle138b binds into a tube-shaped hole inside such a lipidic fibril. The researchers’ findings could pave the way for new approaches to diagnosing and treating Parkinson’s disease, as now presented in two publications in the journal Nature Communications.


Alpha-synuclein proteins (green) form long helical fibrils (top). When the fibrils form, the proteins extract lipids (grey/red) from lipid membranes (bottom) and integrate them into the fibril structure. (Image: HHU/Benedikt Frieg)

It is a disease with many faces: In the progressive stage of Parkinson’s, limbs begin to tremble, muscles become stiff, movements slow down. In some cases, cognitive disorders or depression occur. There is currently no cure for Parkinson’s, which is a so-called alpha-synucleinopathy, as are the related diseases Lewy body dementia and multisystem atrophy.

Conspicuous deposits in the brain

A striking feature of Parkinson’s disease and other alpha-synucleinopathies is clumps of alpha-synuclein proteins in the brain. Like other proteins, alpha-synuclein consists of long chains of amino acids that must fold correctly in three dimensions to fulfil their functions. In the wrong shape, they can “stack up” to form thread-like structures – so-called fibrils. The fibrils, in turn, can form even larger aggregates. Scientists suspect that the accumulation of misfolded alpha-synuclein proteins impairs the function of nerve cells and contributes to their death.

In its correct folding, however, alpha-synuclein is indispensable for nerve cells. It binds to lipid membranes and is involved in transporting vesicles and releasing the messenger substances they carry in nerve cells.  

“However, lipids also appear to interact with misfolded alpha-synucleins,” reports Professor Dr Gunnar Schröder, leader of the “Computational Structural Biology Group” at FZJ and professor at Heinrich Heine University Düsseldorf. It has long been suspected that interactions between lipids and misfolded alpha-synuclein proteins could play a role in the development of Parkinson’s disease. Until now, however, there have been very few more precise findings to back this up.

Lipids influence fibril formation

The scientists have now been able to close this knowledge gap. Using cryo-electron microscopy, they succeeded in visualising for the first time how lipid molecules bind to the fibril surface and connect the units with each other. By using sophisticated computer simulations combined with solid-state nuclear magnetic resonance spectroscopy, the teams were also able to show how the lipid and protein elements interact within fibrils.

Surprisingly for the research teams, several completely novel fibrils formed in the presence of lipids. “Our findings underline that we also need to study alpha-synuclein fibrils in the presence of lipids if we want to understand the molecular basis of alpha-synuclein-related pathologies,” Max Planck Director, Professor Dr Christian Griesinger, comments.

Parkinson’s drug candidate anle138b binds to lipid fibrils

“The promising drug candidate anle138b also binds to lipidic alpha-synuclein structures. The drug attaches to the tubular cavities within the lipidic fibril,” says Dr Loren Andreas, research group leader at the MPI. “We also find such cavities in other proteins that misfold and are associated with neurodegenerative diseases, for example the tau and prion proteins. The exciting question for us now is whether anle138b attaches there in a similar way and could therefore also provide a therapeutic approach for such diseases.”

Original publications

Frieg, B.; Antonschmidt, L.; Dienemann, C.; Geraets, J. A.; Najbauer, E. E.; Matthes, D.; de Groot, B. L.; Andreas, L. B.; Becker, S.; Griesinger, C. and Schröder, G. F.: The 3D structure of lipidic fibrils of α-synuclein. Nature Communications, Nature Commun 13, 6810 (2022).

DOI: 10.1038/s41467-022-34552-7

Antonschmidt, L.; Matthes, D.; Dervişoğlu, R.; Frieg, B.; Dienemann, C.; Leonov, A.; Nimerovsky, E.; Vrinda Sant, V.; Ryazanov, S.; Giese, A.; Schröder, G. F.; Becker, S.; de Groot, B. L.; Griesinger, C. and Andreas, L. B.: The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils. Nature Commun, 13, 1-10 (2022).

DOI: 10.1038/s41467-022-32797-w

Kategorie/n: Schlagzeilen, Pressemeldungen, Auch in Englisch, Math.-Nat.-Fak.-Aktuell, Forschung News, Forschungsnews Englisch
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