{"id":30360,"date":"2021-04-07T00:00:29","date_gmt":"2021-04-07T07:00:29","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=30360"},"modified":"2024-01-30T14:36:04","modified_gmt":"2024-01-30T22:36:04","slug":"parkinsons-cancer-type-2-diabetes-share-a-key-element-that-drives-disease","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/parkinsons-cancer-type-2-diabetes-share-a-key-element-that-drives-disease\/","title":{"rendered":"Parkinson\u2019s, cancer, type 2 diabetes share a key element that drives disease"},"content":{"rendered":"

LA JOLLA\u2014When cells are stressed, chemical alarms go off, setting in motion a flurry of activity that protects the cell\u2019s most important players. During the rush, a protein called Parkin hurries to protect the mitochondria, the power stations that generate energy for the cell. Now Salk researchers have discovered a direct link between a master sensor of cell stress and Parkin itself. The same pathway is also tied to type 2 diabetes and cancer, which could open a new avenue for treating all three diseases.<\/p>\n

\u201cOur findings represent the earliest step in Parkin\u2019s alarm response that anyone’s ever found by a long shot. All the other known biochemical events happen at one hour; we’ve now found something that happens within five minutes,\u201d says Professor \u9c81\u672c-\u8096<\/a>, director of the NCI-designated Salk Cancer Center and senior author of the new work, detailed in Science Advances<\/em><\/a> on April 7, 2021. \u201cDecoding this major step in the way cells dispose of defective mitochondria has implications for a number of diseases.\u201d<\/p>\n

\"Parkin
Parkin protein (green signal) is in a different part of the cell than the mitochondria (red signal) at time 0 (left image) but then co-localizes with the mitochondria after 60 minutes (right image).
Click here<\/a> for a high-resolution image.
Credit: Salk Institute<\/figcaption><\/figure>\n

Parkin\u2019s job is to clear away mitochondria that have been damaged by cellular stress so that new ones can take their place, a process called mitophagy. However, Parkin is mutated in familial Parkinson\u2019s disease, making the protein unable to clear away damaged mitochondria. While scientists have known for some time that Parkin somehow senses mitochondrial stress and initiates the process of mitophagy, no one understood exactly how Parkin was first sensing problems with the mitochondria\u2014Parkin somehow knew to migrate to the mitochondria after mitochondrial damage, but there was no known signal to Parkin until after it arrived there.<\/p>\n

Shaw\u2019s lab, which is well known for their work in the fields of metabolism and cancer, spent years intensely researching how the cell regulates a more general process of cellular cleaning and recycling called autophagy. About ten years ago, they discovered that an enzyme called AMPK, which is highly sensitive to cellular stress of many kinds, including mitochondrial damage, controls autophagy by activating an enzyme called ULK1.<\/p>\n

Following that discovery, Shaw and graduate student Portia Lombardo began searching for autophagy-related proteins directly activated by ULK1. They screened about 50 different proteins, expecting about 10 percent to fit. They were shocked when Parkin topped the list. Biochemical pathways are usually very convoluted, involving up to 50 participants, each activating the next. Finding that a process as important as mitophagy is initiated by only three participants\u2014first AMPK, then ULK1, then Parkin\u2014was so surprising that Shaw could scarcely believe it.<\/p>\n

To confirm the findings were correct, the team used mass spectrometry to reveal precisely where ULK1 was attaching a phosphate group to Parkin. They found that it landed in a new region other researchers had recently found to be critical for Parkin activation but hadn\u2019t known why. A postdoctoral fellow in Shaw\u2019s lab, Chien-Min Hung, then did precise biochemical studies to prove each aspect of the timeline and delineated which proteins were doing what, and where. Shaw\u2019s research now begins to explain this key first step in Parkin activation, which Shaw hypothesizes may serve as a \u201cheads-up\u201d signal from AMPK down the chain of command through ULK1 to Parkin to go check out the mitochondria after a first wave of incoming damage, and, if necessary, trigger destruction of those mitochondria that are too gravely damaged to regain function.<\/p>\n

The findings have wide-ranging implications. AMPK, the central sensor of the cell\u2019s metabolism, is itself activated by a tumor suppressor protein called LKB1 that is involved in a number of cancers, as established by Shaw in prior work, and it is activated by a type 2 diabetes drug called metformin.\u00a0 Meanwhile, numerous studies show that diabetes patients taking metformin exhibit lower risks of both cancer and aging comorbidities. Indeed, metformin is currently being pursued as one of the first ever \u201canti-aging\u201d therapeutics in clinical trials.<\/p>\n

\u201cThe big takeaway for me is that metabolism and changes in the health of your mitochondria are critical in cancer, they’re critical in diabetes, and they’re critical in neurodegenerative diseases,\u201d says Shaw, who holds the William R. Brody Chair. \u201cOur finding says that a diabetes drug that activates AMPK, which we previously showed can suppress cancer, may also help restore function in patients with neurodegenerative disease. That\u2019s because the general mechanisms that underpin the health of the cells in our bodies are way more integrated than anyone could have ever imagined.\u201d<\/p>","protected":false},"featured_media":30364,"template":"","faculty":[45],"disease-research":[46,146,123],"class_list":["post-30360","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-reuben-shaw","disease-research-cancer-biology","disease-research-aging-and-regenerative-medicine","disease-research-metabolism-and-diabetes"],"acf":[],"yoast_head":"\nParkinson\u2019s, cancer, type 2 diabetes share a key element that drives disease - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/parkinsons-cancer-type-2-diabetes-share-a-key-element-that-drives-disease\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Parkinson\u2019s, cancer, type 2 diabetes share a key element that drives disease - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014When cells are stressed, chemical alarms go off, setting in motion a flurry of activity that protects the cell\u2019s most important players. 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