Parkinson’s disease(Parkinson’s disease) is the most common neurodegenerative disease other than Alzheimer’s disease. Although the cause is not yet clear, α-synuclein in the brain misfolds into thread-like fibril-like structures and, in the event of a formation of aggregates, has been recognized as one of the obvious pathological features.
In the latest study by “Nature Communications”, the German team demonstrated for the first time how lipid molecules bind directly to the surface of fibrils and influence the arrangement of synuclein proteins in the fibrils. While understanding the interaction between lipids and fibrils deepens, the research could open up new ways to diagnose and treat Parkinson’s disease.
Lipids influence fibril formation in alpha-synuclein
Like other proteins, alpha-synuclein is made up of long chains of amino acids that must fold properly in three dimensions to function. When properly folded, α-synuclein binds to lipid membranes and is involved in vesicle transport, the release of message substances, and other functions essential to nerve cells, but if improperly shaped, it accumulates in the fibrils and forms Larger clusters, scientists suspect, are the accumulation of these misfolded alpha-synuclein proteins leading to impaired function and even death of nerve cells.
In previous studies, the interaction between lipids and α-synuclein fibrils was identified as related to Parkinson’s disease pathology, but the actual interaction process is still unknown, so the team specifically introduced cryo-electron microscopy technology ( cryo-EM), in the new study clarified for the first time the structure of six fibrils of α-synuclein in complex with lipids.
Using complex computer simulations and solid-state nuclear magnetic resonance (MSN), the team also further explored the details of the interaction between lipids and proteins within the fibrils; Compared with normal fibrils, lipid-complexed α-synuclein significantly enhanced, suggesting that membrane interactions may play a key role in fibril packing.
Alpha-synuclein research should take lipids into account
About 6 million people worldwide suffer from Parkinson’s disease, but there is still a lack of effective treatments, dementia with Lewy bodies and degenerative multiple system diseases (multiple system atrophy) and no cure has been found.
Considering that several completely new fibrils are formed in the presence of lipids, study author Christian Griesinger, director of the Max Planck Institute (Max Planck Institute), believes that future researchers who want to understand the molecular basis of the pathology in question should rely On the presence of It is necessary to study α-synuclein fibrils in the absence of lipids.
In testing anle138b, a clinical drug candidate for neurodegenerative diseases, the team found that anle138b also binds to lipid α-synuclein structures, attaching to tubular lumens within the fibrils, where tau proteins, proteins associated to neurodegenerative diseases, such as prion protein, have also found the same cavity and the team plans to continue to explore whether anle138b and other drugs attach to it similarly in the future, so as to provide diagnosis and treatment for such methods of diseases.
References:
1. Nature Communications, 2022,https://doi.org/10.1038/s41467-022-32797-w
2. Nature Communications, 2022,https://doi.org/10.1038/s41467-022-34552-7
3. https://www.mpinat.mpg.de/4254758/pr_2233
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