In Parkinson’s disease, the most common neurodegenerative disorder after Alzheimer’s, although the cause is unknown, alpha-synuclein in the brain turns into fibril-like threads A shaped structure, and eventually the formation of aggregates, has ‘to be recognized as one of the prominent pathological features. .
In the latest study from “Nature Communications”, the German team showed for the first time how lipid molecules bind directly to the surface of fibrils and affect the arrangement of synuclein proteins in the fibrils. As the understanding of the interaction between lipids and fibrils deepens. , the research may open up new ways of diagnosing and treating Parkinson’s disease.
Lipids affect fibril formation in alpha-synuclein
Like other proteins, alpha-synuclein consists of long chains of amino acids that must fold correctly in three dimensions to function. When properly folded, α-synuclein binds to lipid membranes and is involved in vesicle transport, the release of messenger substances, and other functions essential to nerve cells, but when it is improperly shaped, it accumulates into fibrils and forms larger aggregates, scientists suspect, is the accumulation of these misfolded alpha-synuclein proteins that leads to impaired function and even death of nerve cells.
In previous studies, it was noted that the interaction between lipids and α-synuclein fibrils is associated with the pathology of Parkinson’s disease, but the actual interaction process is still unknown, so the team introduced cryo-electron microscopy (cryo-EM) technology in specifically, the new study elucidated the structure of six α-synuclein fibrils in complex with lipid for the first time.
Using complex computer simulations and solid state magnetic resonance (solid state magnetic resonance), the team further explored the details of the interaction between lipids and proteins within fibrils; compared to ordinary fibrils, lipid-complexed α-synuclein fibrils were significantly enhanced, suggesting that membrane interactions may play a key role in fibril packing.
Alpha-synuclein research should consider lipids
Around 6 million people in the world suffer from Parkinson’s disease, but there is still a lack of effective treatments, Lewy body dementia and multiple system degenerative diseases (Multiple system atrophy) and no cure has been found.
Given that a number of entirely 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 relevant pathology must depending on the presence α-synuclein fibrils need to be studied in the absence of lipids.
When testing anle138b, a clinical drug candidate for neurodegenerative diseases, the team found that anle138b also binds to α-synuclein lipid structures, connecting to tubular lumens within fibrils, where tau proteins, Proteins associated with 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 are related to it in a similar way in the future, in order to provide diagnosis and treatment on for such diseases method.
Further reading: A new development in the diagnosis of Parkinson’s disease! New MIT study: Detecting sleep breathing can track disease progression
Addresses:
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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