Research on compounds activating autophagy in neural stem cells derived from iPS cells
2023 年 11 巻 1 号 p. 1-7
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2023 年 11 巻 1 号 p. 1-7
Autophagy activity of cranial nerves can decline as a result of aging, resulting in the onset of various neurodegenerative diseases. Defects or disruptions in autophagy are thought to allow aggregation of misfolded proteins leading to neurodegeneration. Acid β-glucosidase (GBA) is a lysosome enzyme that plays an important role in autophagy. Deficiency of GBA causes defects of neuronal autophagy including the accumulation of abnormal proteins. However, direct effects of GBA activation on autophagy are not yet understood. Induced pluripotent stem cells (iPSCs) can differentiate into various living cells and are expected to be applied to regenerative medicine and the treatment of disease-relevant cells, such as neurons. To explore the mechanism of autophagy and identify small molecules that activate autophagy, we screened small molecule regulators of autophagy in iPSCs: coreajaponin, dioscin and diosgenin. This series of screens allowed us to distinguish between compounds that can induce autophagic degradation and compounds that induce autophagosome accumulation as a result of causing cytotoxicity or inhibiting downstream lysosomal function. Our analyses led to the identification of compounds that can induce autophagy and activate GBA. Among the tested compounds, coreajaponin increased cell proliferation and intracellular GBA activity, and maintained the autolysosome formation activity in neural stem cells (NSC). In conclusion, coreajaponin could be suitable for the activation of autophagy and have potential therapeutic implications for common neurodegenerative diseases.
