Parkinson’s research: lipids influence the structure of protein clumps
After Alzheimer’s disease, Parkinson’s is the most common neurodegenerative disease worldwide. Up to 400,000 people suffer from it in Germany alone. Defective alpha-synuclein proteins form fibrous strands. When these so-called fibrils clump together, they presumably damage nerve cells. A research team from the Max Planck Institute for Multidisciplinary Natural Sciences in Göttingen, Heinrich Heine University Düsseldorf (HHU) and 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 they demonstrated, the drug candidate anle138b binds into a tube inside such a lipidic fibril. Their findings could open up new approaches to diagnosing and treating Parkinson’s disease, as now presented in two publications in the journal Nature Communications. (Source: Forschungszentrum Jülich – Press Releases)
It is a disease with many faces: As Parkinson’s progresses, limbs begin to tremble, muscles become stiff, and movements slow down. Cognitive disorders or depression can also occur. Currently, Parkinson’s is not curable. Together with Lewy body dementia and multisystem atrophy, the disease belongs to the so-called alpha-synucleinopathies.
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, these are made up of long amino acid chains that must fold correctly in three dimensions to do their jobs. In the wrong shape, alpha-synuclein proteins can “stack” on top of each other to form thread-like strands called fibrils. The fibrils, in turn, can form even larger deposits. Researchers suspect that conglomerations of misfolded alpha-synuclein proteins impair nerve cell function and contribute to their death.
In its correct folding, however, alpha-synuclein is indispensable for the nerve cell. It binds to lipid membranes and, in nerve cells, is involved in transporting messenger containers and releasing messenger substances contained within them.
“However, lipids also appear to interact with misfolded alpha-synucleins,” reports Prof. Dr. Gunnar Schröder, head of the “Computational Structural Biology Group” at FZJ and professor at Heinrich Heine University Düsseldorf. That interactions between lipids and misfolded alpha-synuclein proteins could play a role in the development of Parkinson’s disease has long been suspected. But until now, there has been little more detailed knowledge about this.
Lipids influence fibril formation
The scientists have now been able to close this knowledge gap. They succeeded in using cryo-electron microscopy to visualize for the first time how lipid molecules attach to the fibril surface and bind the units together. By using sophisticated computer simulations combined with solid-state nuclear magnetic resonance spectroscopy, the teams were also able to visualize how lipid-protein fibrils interact with each other.
Surprisingly for the research teams, several completely novel fibrils formed in the presence of lipids. “Our findings underscore that we need to study alpha-synuclein fibrils even in the presence of lipids if we want to understand the molecular basis of alpha-synucleinopathies,” reports Max Planck Director Prof. Christian Griesinger.
Parkinson’s drug candidate anle138b binds to lipid fibrils
“The promising drug candidate anle138b also binds to lipid alpha-synuclein structures. The drug attaches to the tubular cavities within the lipid fibril,” pointed out Dr. Loren Andreas, research group leader at MPI. “We also find such cavities in other proteins that misfold and are associated with neurodegenerative diseases, for example, the tau protein and the prion protein. The exciting question for us now is whether anle138b accumulates there in a similar way and could thus also provide a therapeutic approach for such diseases.”
The original press release can be found at:
Parkinson-Forschung: Lipide beeinflussen Aufbau von Protein-Verklumpungen (only in german)
The original publication can be found at:
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, 5385 (2022). DOI: 10.1038/s41467-022-32797-w
Localization in the Helmholtz Research Field Information:
Helmholtz Research Field Information, Program 2: Natural, Artificial and Cognitive Information Processing, Topic 4: Molecular and Cellular Information Processing
Contact:
Prof. Dr. Gunnar Schröder
Institute of Biological Information Processing (IBI)
Structural Biochemistry (IBI-7)
Forschungszentrum Jülich
Tel.: +49 2461/61-3259
E-Mail: gu.schroeder@fz-juelich.de
Contact for this press release:
Dr. Regine Panknin
Press Officer
Forschungszentrum Jülich
Phone: +49 2461 61-9054
E-Mail: r.panknin@fz-juelich.de
