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▎ WuXi AppTec content team editor
Parkinson's disease currently plagues more than 6 million patients worldwide, and the distinctive feature of the disease is abnormal α-synuclein clumps in the brain
。 α-synuclein, like other proteins, is composed of long-chain amino acids, which also require amino acids to be folded correctly to function
.
If there is a problem with this process, they stack up to form fibrils
.
Then, like a snowball, fibril aggregates grow larger and larger, eventually impairing nerve cell function and leading to cell death
.
But the brain is inseparable from the properly folded α-synuclein, so treatment cannot simply and crudely remove this protein
.
Scientists would like to know what mechanisms play a role when α-synuclein misfolds so they can try to block this erroneous behavior, but progress is still very limited
.
A study in Nature Communications noted that α-synuclein binds to lipid membranes and participates in vesicle trafficking, which is essential
for transmitting messenger molecules.
Therefore, the authors were also curious about whether lipids were involved in the misfolding process
.
▲ Lipids have an important supporting effect on the structure of fibrils (green) (Image source: Benedikt Frieg) With the help of cryo-electron microscopy, they successfully observed the process of binding lipids to the surface of fibrils, and it can be seen in the reduction map that during the formation of fibrils, proteins will continue to obtain lipids from the lipid membrane, and then transfer them to fibrils, and finally form a complete fibril structure
。 In another Nature Communications paper, the team found that a potential drug, ANLE138B, could bind to a tubular cavity formed by fibrils and lipids, "This cavity structure is actually found in other misfolded proteins, such as tau, and ANLE138B has the potential to
treat more neurodegenerative diseases.
" Dr Loren Andreas, one of the study leaders, said
.
In mouse tests, ANLE138B successfully delayed the progression of Parkinson's disease, and the research team is currently conducting phase 1 clinical trials for the drug, which is safe in patients from the available data, and the team plans to further promote clinical trials to verify its therapeutic effect
.
Parkinson's disease currently plagues more than 6 million patients worldwide, and the distinctive feature of the disease is abnormal α-synuclein clumps in the brain
。 α-synuclein, like other proteins, is composed of long-chain amino acids, which also require amino acids to be folded correctly to function
.
If there is a problem with this process, they stack up to form fibrils
.
Then, like a snowball, fibril aggregates grow larger and larger, eventually impairing nerve cell function and leading to cell death
.
But the brain is inseparable from the properly folded α-synuclein, so treatment cannot simply and crudely remove this protein
.
Scientists would like to know what mechanisms play a role when α-synuclein misfolds so they can try to block this erroneous behavior, but progress is still very limited
.
A study in Nature Communications noted that α-synuclein binds to lipid membranes and participates in vesicle trafficking, which is essential
for transmitting messenger molecules.
Therefore, the authors were also curious about whether lipids were involved in the misfolding process
.
▲ Lipids have an important supporting effect on the structure of fibrils (green) (Image source: Benedikt Frieg) With the help of cryo-electron microscopy, they successfully observed the process of binding lipids to the surface of fibrils, and it can be seen in the reduction map that during the formation of fibrils, proteins will continue to obtain lipids from the lipid membrane, and then transfer them to fibrils, and finally form a complete fibril structure
。 In another Nature Communications paper, the team found that a potential drug, ANLE138B, could bind to a tubular cavity formed by fibrils and lipids, "This cavity structure is actually found in other misfolded proteins, such as tau, and ANLE138B has the potential to
treat more neurodegenerative diseases.
" Dr Loren Andreas, one of the study leaders, said
.
In mouse tests, ANLE138B successfully delayed the progression of Parkinson's disease, and the research team is currently conducting phase 1 clinical trials for the drug, which is safe in patients from the available data, and the team plans to further promote clinical trials to verify its therapeutic effect
.
Resources:
[1] Benedikt Frieg et al, The 3D structure
of lipidic fibrils of α-synuclein, Nature Communications (2022).
DOI:
10.
1038/s41467-022-34552-7
[2] Leif Antonschmidt et al, The clinical
drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils,
Nature Communications (2022).
DOI: 10.
1038/s41467-022-32797-w
[3] Discovery in Parkinson's research:
Lipids influence the formation of protein clumps.
Retrieved November 17, 2022 from
https://medicalxpress.
com/news/2022-11-discovery-parkinson-lipids-formation-protein.
html
