2021-07-16

Research finds that Parkinson’s disease, cancer and type 2 diabetes share a key factor driving the disease

By yqqlm yqqlm

Research finds that Parkinson’s disease, cancer and type 2 diabetes share a key factor driving the disease

“Our discovery represents the Parkin that people have discovered This is the earliest step in the alert response of the United States, which is a big challenge. All other known biochemical events occurred within one hour; we have now discovered what happened within five minutes,” National Cancer Institute Said Professor Reuben Shaw, appointed director of the Salk Cancer Center and senior author of this new work. This work has been published in “Science Progress” on April 7, 2021. “Decoding this major step in the way cells dispose of defective mitochondria has an impact on some diseases.”

Parkin’s job is to remove mitochondria damaged by cellular stress so that new mitochondria can be created. Can replace it, this process is called mitosis. However, Parkin is mutated in familial Parkinson’s disease, making the protein unable to clear the damaged mitochondria. Although scientists already know that Parkin somehow senses mitochondrial pressure and initiates the process of mitosis, no one knows exactly how Parkin senses the problem of mitochondria in the first place-Parkin somehow knows that mitochondria migrate to mitochondria after damage, but Before Parkin got there, there was no known signal.

Shaw’s laboratory is well-known for its work in the fields of metabolism and cancer, and they have spent years studying in depth how cells regulate a more common cell cleaning and recycling process called autophagy. About ten years ago, they discovered that an enzyme called AMPK is highly sensitive to a variety of cellular stresses (including mitochondrial damage) and controls autophagy by activating an enzyme called ULK1.

After this discovery, Shaw and graduate student Portia Lombardo began looking for autophagy-related proteins that are directly activated by ULK1. They screened about 50 different proteins and estimated that about 10% of them would be suitable. When Parkin topped the list, they were shocked. Biochemical pathways are usually very complex, involving up to 50 participants, each of which activates the next. The discovery that an important process like mitosis was initiated by only three participants—first AMPK, then ULK1, and then Parkin—was so surprising that Shaw could hardly believe it.

To confirm that these findings are correct, the research team used a mass spectrometer to accurately reveal where ULK1 attaches a phosphate group to Parkin. They found that it fell in a new area, and other researchers recently discovered that it is essential to Parkin’s activation, but don’t know why. A postdoctoral fellow in Shaw’s lab, Jianmin Hong, then conducted precise biochemical studies to prove every aspect of the timeline and delineate which proteins are doing what and where. Shaw’s research is now beginning to explain this critical first step of Parkin activation. Shaw hypothesized that this may be a “cue” signal sent by AMPK to Parkin through ULK1, that is, to check mitochondria after the first wave of damage, and trigger it if necessary. Damage to mitochondria that are severely damaged and unable to restore function.

This discovery has broad significance. AMPK is the central sensor of cell metabolism. It itself is activated by a tumor suppressor protein called LKB1, which is involved in some cancers. As Shaw has determined in previous work, it is used by a type of type 2 diabetes called metformin. Drug activation. At the same time, many studies have shown that diabetic patients taking metformin exhibit a lower risk of cancer and aging complications. In fact, metformin is currently undergoing clinical trials as one of the first “anti-aging” therapeutic drugs.

“The biggest gain for me is that changes in metabolism and mitochondrial health are critical to cancer, to diabetes, and to neurodegenerative diseases,” William R. Shaw of the Brody Chair said. “Our findings indicate that a diabetes drug that activates AMPK – we have previously shown that it can inhibit cancer and may also help restore the function of patients with neurodegenerative diseases. This is because the general mechanisms that support the health of cells in our body are more than Anyone’s imagination is much more comprehensive.”