动物实验 z-bo 2020-10-09 278

　　Protein misfolding and aggregation are common pathological features of many neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Croyzfeld-Jacob disease and Huntington's disease). Previous studies have shown that α-sucrose has viral properties, but it is not clear whether the difference in α-sucrose aggregates explains the different pathological mechanisms. In a recent study, Suzuki et al. of TMIMS elucidated the possible molecular mechanism to explain the different pathological features caused by different α-synuclein types. First, Suzuki et al. prepared recombinant α-synuclein monomers and stirred them at physiological concentrations in the presence or absence of salt to produce two types of α-synuclein. Fibrils (+) and (-) are both derived from the same monomer. Next, α-synuclein fibrils (+) and α-synuclein fibrils (-) were injected into the striatum of wild-type mice, and after one month, the phosphorylated α synapses were examined. The accumulation of nuclear protein deposits is similar to the accumulation in the patient's brain. They found that α-synuclein fibrils (-) induced abnormal deposition of α-synuclein in the mouse brain, while α-synuclein fibrils (+) caused α-synaptic phosphorylation.

　　In order to further study the differences in the formation of pathological α-sinucrane aggregates in neurons, Suzuki et al. compared two α-sinucrane strains and induced seed-dependent α-n-butane aggregation ability in primary mouse cortical neurons. . They observed that the accumulation of phosphorylated α-sinucrane (-) increased sharply, but the accumulation of α-sinucrane fibrils (+) was small. They also found that in cells treated with α-synuclein fibrils (-), α-synuclein was not only ubiquitinated but also accumulated other ubiquitinated proteins. In the cells treated with protein fibrils (+), the accumulation of ubiquitinated protein did not increase significantly. Suzuki et al. studied the activity of the proteasome in the presence of these two types of α-synuclein fibrils and found that only α-synuclein fibrils (-) significantly inhibited proteases in vitro. physical activities. They also studied the interaction between 26S proteasome and fibrils, and found that α-n-butene fibrils (-) co-precipitated with the purified 26S proteasome complex. These results indicate that only α-synuclein fibrils (-) interact with the 26S proteasome and impair proteasome activity.

　　Next, Suzuki et al. wanted to clarify the structural difference between the two types of α-butadiene fibrils. They studied the core and exposed areas of these α-synuclein fibrils and found that the core area of α-synuclein fibrils (-) is small, while the core of α-synuclein fibrils (+) The area is small. The core area is larger and extends to the C terminal area. This indicates that compared with α-synuclein fibrils (+), α-synuclein fibrils (-) have an amyloid structure with more exposed C-terminal regions. Therefore, they believe that the C-terminal region (-) of α-n-butadiene fibrils may interact with the 26S proteasome and reduce its activity. According to Prion's hypothesis, differences in disease symptoms and pathological changes are caused by differences in the composition of protein aggregates. Therefore, if α-sinucrane is a virus, the structural difference of α-sinucrane aggregates should cause the difference in pathological changes observed in various α-sinucrane diseases. In this study, Suzuki et al. confirmed that two structurally different α-synuclein strains cause different pathologies, and also found that these α-synuclein strains have different abilities to inhibit 26S proteasome activity.

　　A significant finding in this study is that under different conditions, one of the two fibrils with different structures formed by the same monomer inhibits the activity of the proteasome, while the other does not. This obviously increases the possibility that abnormal α-synuclein inhibiting the proteasome will play a role in pathology.