24 May 2022
Rethinking Lewy body dementia
Published online 6 April 2022
A characteristic brain protein in Lewy body dementia could turn out to be defence mechanism against the disease.
Lewy body disease, or dementia with Lewy bodies, is characterised by a brain build-up of a particular form of the protein alpha-synuclein, forming clumps called aggregates. These aggregates are mostly made up of the phosphorylated form of alpha-synuclein, in which a single amino acid – serine 129 – is altered by the addition of a phosphoryl group. However, the biological role that phosphorylated alpha-synuclein plays in Lewy body disease had not been clear.
Now, Omar El-Agnaf, from Hamad Bin Khalifa University in Qatar, and an international team of researchers, including from United Arab Emirates University, have used cell cultures, animal models and post-mortem brain tissue from people with Lewy body disease to reveal when and how these protein aggregates form.
Using antibodies that bind to either the phosphorylated or non-phosphorylated (wild-type) forms of alpha-synuclein, researchers were able to show that the phosphorylated form of the protein actually appears a few weeks after the protein aggregates have begun to form in the brain. This challenges the idea that the phosphorylated form of the protein is the cause of aggregate formation.
“We are missing an early stage of the disease if it starts before the phosphorylation,” El-Agnaf says.
The research team also looked at how well the protein aggregates formed in a test tube when the environment was rich in either the phosphorylated form or the wild-type form of the protein. This revealed that the aggregates formed much more successfully among the wild-type non-phosphorylated form than they did with the phosphorylated form. This raised the possibility that the phosphorylated form of protein might actually be working to inhibit the formation of aggregates, and could even have a protective effect in the brain.
The findings have implications for understanding and diagnosing the disease, and developing treatments for it. Currently, the phosphorylated form of alpha-synuclein is used as a biomarker for Lewy body disease, but El-Agnaf says the findings cast doubt on its value as an early marker of disease.
It could also change therapeutic targets for the disease. “If we want a target, especially at the early stage of the disease, we should target the non-phosphorylated form of the protein… as that may be the pathogenic toxic species,” says El-Agnaf.
Ghanem, S. et al. α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity. PNAS 119, e2109617119 (2022).