Aug 8: Brain cells that release dopamine – a messenger chemical that drives motor control- package it into tiny membrane-bound sacs called synaptic vesicles. And these vesicles differ from vesicles used by brain cells that release other messenger chemicals, a study led by Cedars-Sinai Health Sciences University investigators shows.
The study, published in Science Advances, could lead to better understanding of Parkinson’s disease, a movement disorder that causes dopamine-releasing brain cells to progressively die. The death of these cells leads to the movement problems that characterize the disease.
“Our research sheds light on the different ways brain cells release chemical messengers, which the cells use to communicate with each other,” said Katlin Silm, PhD, assistant professor of Biomedical Sciences and Neurology and senior author of the study. “We identified key differences between brain cells that release dopamine and those that release other brain chemicals.”
Synaptic vesicles help brain cells to communicate by fusing with the cell membrane and releasing their contents into the space between cells. In the brains of laboratory mice, investigators found that dopamine-containing synaptic vesicles carry a distinct set of proteins compared to those containing other messenger chemicals.
“Our findings show that a vesicle’s composition is critical to determining how brain messenger chemicals are released,” said Silm, also a research scientist in the Board of Governors Regenerative Medicine Institute. “The differences we identified help explain the unique properties of dopamine release and lay the groundwork to explore how this affects the long-term stability of dopamine-producing brain cells.”
Additional Cedars-Sinai authors include Hrach Asmerian, Alexia J. Diaz, Jacob Alberts, Barathan Gnanabharathi, Anna M. Sanetra, and Noah Carr.
Other authors include Hongfei Xu, Juan A. Oses-Prieto, Poulomi Das, Alma L. Burlingame, and Robert H. Edwards.
Funding: This work was supported by The Larry L. Hillblom Foundation grant 2022-A-004-SUP (KS), Brain and Behavior Research Foundation grant 29845 (KS), National Institutes of Health grant R01NS138465 (KS), National Institutes of Health grant R01NS103938 (RHE), National Institutes of Health grant R01NS129803 (RHE). Mass spectrometry was performed at the Mass Spectrometry Resource at UCSF, which is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (JAO-P & ALB).
New Method Could Boost Blood Tests’ Colon Cancer Monitoring Value
Blood tests could become a more powerful tool for monitoring colon cancer progression and treatment response, based on a study led by Cedars-Sinai Health Sciences University investigators. Their findings, published in Experimental Hematology & Oncology, used single-cell profiling to analyze circulating tumor cells and noncancerous cells in patients’ blood.
“Our method looks beyond the tumor to also understand the patient’s response to the cancer,” said Jun Gong, MD, medical director of Colorectal Cancer at Cedars-Sinai and an author of the study. “It could help guide more personalized treatment decisions based on tumor behavior and patient condition.”
Investigators analyzed blood samples from patients with advanced colorectal cancer, looking at 10 different cellular characteristics and using single-cell analysis to refine their findings.
The method reveals important changes, such as tumor cells taking action to evade the immune system or normal cells showing inflammation. These changes would be missed with existing tests, Gong said.
If these findings are validated in larger studies, Gong said, this method would complement existing tools for cancer monitoring, including imaging and standard laboratory tests.
Additional Cedars-Sinai authors include Francesca Aguirre, MD; Lisa Zhou, BS; Aaron Denmark, BS; Rocio Alvarez, MsC; and Daniel M. Kim, MD.
Other authors include Gabriela Felix, PhD; and Megan P. Hitchins, PhD.
Funding: This study was funded in part by NCI grant R01CA252042 (MH), Cedars-Sinai Cancer Developmental Fund (MH) and the ASCO Conquer Cancer Career Development Award.ing fees and honoraria from the following companies: EMD Serono, Exelixis, Natera, Eisai, Janssen, Pfizer, Bayer, Taiho, Agenus, Seagen, and Caper Labs. G.F., J.G. and M.H. have a provisional patent application (Application No.: 64/039,184) related to the work described in this manuscript.
Hydrogen Sulfide Gas Linked to More Severe IBS Damage
Investigators at Cedars-Sinai Health Sciences University have identified how excess hydrogen sulfide gas produced by certain gut microbes alters gene activity in the small intestine. Their findings, published in mSystems, offer new insight into conditions associated with irritable bowel syndrome (IBS), one of the most common gastrointestinal disorders.
Small intestinal bacterial overgrowth , intestinal methanogen overgrowth and intestinal sulfide overproduction are conditions in which gas-producing microbes over-multiply in the small intestine. The disorders are often connected to IBS.
“Our results show that ISO, IMO and SIBO are biologically distinct conditions that will require different treatment approaches,” said Mark Pimentel, MD, executive director of the Medically Associated Science and Technology Program at Cedars-Sinai and corresponding author of the study. “The genes altered in these conditions are linked to a variety of symptoms and understanding these mechanisms will help us develop better therapies for patients.”
Investigators analyzed small bowel tissues samples from patients and laboratory animals. They found the most extensive changes in gene activity in samples from patients with ISO, and more limited changes in SIBO and IMO samples.
The genetic changes affected immune activity, fluid absorption, movement of nutrients through the gut, antioxidant defenses and cellular energy production. These findings may help explain why hydrogen sulfide overproduction has been associated with diarrhea, abdominal pain and other severe gastrointestinal symptoms in patients with diarrhea-predominant IBS.
Pimentel said larger studies integrating breath testing and microbiome profiling are needed to further validate these findings and identify how they might inform new therapies.
Other Cedars-Sinai authors include Juliana de Freitas Germano, Gabriela Leite, Maria Jesus Villanueva-Millan, Daniel Brimberry, Mohamad Rashid, Ava Hosseini, Dilara Flora, Said Bogatyrev, Walter Morales, Stacy Weitsman, Maritza Sanchez, Ignacio Rivera, Cristina Moreno Fajardo, Victoria Murray, Gonzalo Parodi, Margie Parra, Gillian M. Barlow, Ali Rezaie and Ruchi Mathur.
Other authors include Zhe Lyu.
Funding: This study was primarily supported by the Medically Associated Science and Technology Program at Cedars-Sinai Medical Center, Los Angeles, CA, and funded in part through private donations to the MAST Program.
Disclosures: Drs. Pimentel, Mathur and Rezaie report equity in APQ Health and have received licensing or consulting fees related to diagnostic breath-testing technologies from Gemelli Biotech and Brio-Medical. The remaining authors declare no competing interests.
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