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A new analysis has elucidated the structure and activation mechanisms of the human receptor HCAR1, which is involved in many metabolic and inflammatory conditions. By teasing apart the mechanisms of the receptor’s activation, the findings could inform research into therapies that target HCAR1. This receptor is found in fat, neurons, skeletal muscle, and other tissue types, and fills various roles in metabolism and in reducing inflammation. The receptor’s wide-ranging functions suggest that it could be a solid target in cancer and stroke, as well as in neurodegenerative conditions such as Alzheimer’s disease. However, there are still no potent activators or inhibitors of HCAR1, and scientists know little about how the receptor recognizes its binding partners and becomes activated. Here, Mengru Gao and colleagues harnessed cryo-electron microscopy to interrogate the structure and function of HCAR1 in complex with the G protein subunit Gα_i1. They studied HCAR1 in its unbound state and when it was bound to either lactate – its normal metabolite ligand – or a synthetic activator named CHBA. The authors found that HCAR1 had a smaller and more compact ligand-binding pocket compared with those of other HCARs, such as HCAR2. Lactate bound fairly weakly to HCAR1 and only activated the receptor at relatively high concentrations, but CHBA was more potent and bound more stably. Further research revealed that HCAR1 became self-activated through structural rearrangement of its extracellular loop 2 region. “This study fills gaps in our knowledge of the structure of HCAR1 and elucidates the differences between self-activation and ligand-dependent activation of the receptor, potentially providing a structural and theoretical basis for the design of inverse, selective, and high-efficiency agonists,” the authors conclude.

A groundbreaking international study has demonstrated that Alzheimer's disease biomarkers can be accurately detected using simple finger-prick blood samples that can be collected at home and mailed to laboratories without refrigeration or prior processing.

Researchers at the Technion–Israel Institute of Technology have uncovered a surprising mechanism that may help explain how Alzheimer’s disease spreads through the brain. A cellular system designed to protect neurons by removing toxic proteins may, under certain conditions, actually facilitate the spread of those proteins to neighboring cells—accelerating disease progression.

The study, published in PNAS, was led by Prof. Michael Glickman, Dean of the Technion’s Faculty of Biology, together with Dr. Ajay Wagh. The researchers focused on UBB+1, a defective and toxic form of ubiquitin—a protein normally responsible for marking damaged proteins for degradation.

In healthy cells, toxic proteins are typically broken down internally. However, the team discovered that brain cells sometimes export UBB+1 outside the cell instead of destroying it. This process is mediated by p62, a protein involved in autophagy, the cell’s self-cleaning system. While p62 can direct toxic proteins to the cell’s recycling center (the lysosome), it can also package them into vesicles that are secreted into the extracellular brain fluid.

Once outside the cell, fragments of UBB+1 can leak into neighboring neurons, potentially spreading toxic protein aggregates across brain tissue. This finding may help explain how Alzheimer’s, which can begin in isolated neurons, gradually affects large regions of the brain.

“We all want someone to take out the trash,” says Prof. Glickman, “but in this case, the cells are dumping their trash on their neighbors.”

The discovery could pave the way for earlier diagnosis of Alzheimer’s through fluid biomarkers and for the development of targeted, personalized treatments.

The study was supported by the Israel Science Foundation (ISF) and the European Research Council (ERC).