Protein deformation causes disease differences

As the saying goes, a mouse shit breaks a pot of porridge, and some abnormal proteins in the brain are like this. These misfolded proteins will cause misfolding of nearby proteins. Recently, a new study funded by NIH showed that a protein can form multiple abnormal forms, which have different patterns of influence on other proteins, resulting in corresponding neurological diseases. The research, published in this issue of Cell, has brought important implications for the treatment of Parkinson's disease and other neurodegenerative diseases.

Alpha-synuclein accumulates in brain cells and causes synucleinopathy, multiple system atrophy, Parkinson's disease, Parkinson's disease dementia PDD, and Lewy dementia DLB and other diseases. In these diseases, sometimes other misfolded proteins accumulate. For example, in the brains of PDD and DLB patients, tangles formed by tau protein often appear, which is a sign of Alzheimer's disease. This new study points out that a specific form of α-synuclein causes the simultaneous accumulation of synuclein and tau protein in the brains of patients with PDD and DLB.

Dr. Jing L. Guo and his colleagues prepared α-synuclein fibers with different structures in vitro, and analyzed the effects of these α-synuclein proteins in cell experiments and mouse experiments. They found that the two structures of α-synuclein have very different activities in neurons: one (strain A) only causes the accumulation of α-synuclein, while the other (strain B) causes α-synuclein and tau protein accumulate at the same time.

The researchers constructed a mouse model that can synthesize a large amount of human tau protein and inject the two α-synuclein proteins into the mouse brain. Subsequently, they selected different time points to monitor the accumulation of α-synuclein and tau protein. Studies have shown that compared with mice injected with strain A, the brain of mice injected with strain B has more significant accumulation of tau protein, not only earlier but also across more brain regions.

The researchers also tested brain samples from five PDD patients, some of whom also had Alzheimer's disease. They found two different structures of α-synuclein in these samples, one in the brain of patients with PDD and one in the brain of patients with PDD / Alzheimer's disease.

The two α-synuclein proteins in this study were artificially synthesized, but the authors emphasized that the human brain environment is very complex and there is a chance to form α-synuclein with multiple structures. "These structurally abnormal proteins can not only transform normal α-synuclein in cells into pathogenic proteins, but also spread between cells and change their structural morphology at the same time. The new structural morphology can confer α- Synuclein proteins impair the ability of other proteins, "said Dr. Virginia MY Lee, senior author of the article.

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