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Associated Press
4 days ago
- Health
- Associated Press
Engineered ion channel offers precise, non-invasive control of brain activity
FAYETTEVILLE, GA, UNITED STATES, May 30, 2025 / / -- In a breakthrough advancement for neuroscience, researchers have developed RADICAL, a cutting-edge chemogenetic tool that allows for the precise manipulation of neuronal activity using a synthetic chemical, cyclohexanol ( CHXOL ). Unlike traditional methods that rely on invasive optics or slow-acting G-protein coupled receptors, RADICAL utilizes a modified TRPM8 ion channel to enable rapid and targeted control of calcium influx in neurons. This innovative tool has the potential to advance brain function research and open up new therapeutic possibilities for neurological disorders. Current technologies for controlling neuronal activity—such as optogenetics and chemogenetics—have their limitations. Optogenetics requires invasive light delivery, while chemogenetic systems like DREADDs rely on slow and indirect cellular signaling pathways. Additionally, engineered ligand-gated ion channels, such as those based on nicotinic receptors, can result in unintended interactions with native proteins. These challenges have highlighted the need for a more efficient, non-invasive, and precise method of modulating neuronal excitability. In response to this gap, researchers sought to develop RADICAL, a novel chemogenetic tool that addresses these limitations. In a letter (DOI: 10.1093/procel/pwae048 ) published on September 3, 2024, in Protein & Cell, a team from Zhejiang University unveiled RADICAL, an engineered ion channel activated by cyclohexanol (CHXOL). By introducing specific mutations to the TRPM8 ion channel, they created a system that responds with exceptional sensitivity and specificity to CHXOL. This innovation allows for precise neuronal control without interfering with the brain's native functions, marking a significant step forward in chemogenetics. The key modification in RADICAL was the engineering of the TRPM8 ion channel, which is naturally expressed at low levels in the brain, minimizing potential disruptions to endogenous systems. The team introduced two critical mutations (I846F and I985K) to the TRPM8 ion channel. The I846F mutation restored CHXOL binding, while I985K enhanced voltage sensitivity, enabling robust activation even at hyperpolarizing potentials (-80 mV). Patch-clamp recordings and calcium imaging confirmed the double mutant, TRPM8-I846F-I985K's EC50 of 1.17 mmol/L for CHXOL at depolarizing potentials (+80 mV). In vivo, RADICAL demonstrated its potential: CHXOL administration enhanced fear extinction memory in mice by activating neurons in the infralimbic cortex (IL), and also increased locomotor activity when expressed in astrocytes of the ventral tegmental area (VTA). Importantly, the tool's calcium permeability and minimal cell death risk, as shown in HEK293T cells, suggest its suitability for studying calcium-dependent processes such as learning and memory. Dr. Fan Yang, one of the co-corresponding authors of the study, said: RADICAL represents a major breakthrough in chemogenetics. Its ability to modulate neuronal activity with high precision and minimal off-target effects makes it a versatile tool for both basic neuroscience research and the development of therapeutic interventions. With its non-invasive approach and high specificity, RADICAL has substantial potential in both research and clinical settings. It could enhance our understanding of neurological conditions such as memory disorders, addiction, and mood disorders by providing a precise way to manipulate neuronal circuits. Furthermore, future efforts to miniaturize the tool for adeno-associated virus (AAV) delivery could broaden its applicability in gene therapy. RADICAL's unique combination of speed, specificity, and safety positions it as a powerful platform for next-generation treatments of brain diseases. References DOI 10.1093/procel/pwae048 Original Source URL Funding Information This work was supported by funding from the National Natural Science Foundation of China (32122040 and 31971040 to F.Y.; 32071017 and 31922031 to Y.C.); Zhejiang Provincial Natural Science Foundation of China (LR20C050002 to F.Y.); China Postdoctoral Program for Innovative Talents (BX20230323 to H.Z.); China Postdoctoral Science Foundation (2024M752858 to H.Z.); The Fundamental Research Funds for the Central Universities (226-2022-00227 to F.Y.; 226-2022-00149 to Y.C.); Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions (NYKFKT2019001 to Y.C.); The Fundamental Research Funds for the Central Universities (226-2022-00227 to F.Y.). Lucy Wang BioDesign Research email us here Legal Disclaimer: EIN Presswire provides this news content 'as is' without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.
Associated Press
03-03-2025
- Health
- Associated Press
Unlocking a new path to AML treatment: targeting the JMJD1C-RUNX1 axis for leukemia progression control
/ -- A new study has identified a critical mechanism that could lead to substantial advancements in the treatment of acute myeloid leukemia ( AML). Researchers have discovered that the protein JMJD1C plays a pivotal role in leukemia cell survival. Specifically, JMJD1C is recruited by RUNX1 to genomic loci, where it forms liquid-like condensates. This interaction activates key genes essential for the proliferation and survival of AML cells. The findings offer a promising new strategy to target the transcriptional programs driving leukemia, potentially overcoming the disease's notorious heterogeneity. Acute myeloid leukemia (AML) is one of the most aggressive and genetically complex cancers, marked by the unchecked growth of immature myeloid cells. Its diversity stems from numerous genetic alterations that disrupt normal blood cell development, presenting significant challenges in developing effective, universal therapies. While current treatments often target specific genetic abnormalities, they fall short of addressing the underlying transcriptional networks that sustain leukemia. Uncovering shared vulnerabilities across AML subtypes has become a pressing priority to devise more inclusive and effective therapeutic strategies. In a study (DOI: 10.1093/procel/pwae059) published on October 25, 2024, in the journal Protein & Cell, researchers from Tsinghua University and The Rockefeller University revealed an unprecedented role for JMJD1C in regulating gene expression in AML cells. By interacting with RUNX1, a critical transcription factor, JMJD1C drives leukemia cell survival, making it a compelling therapeutic target. This discovery sheds light on how molecular mechanisms underpinning AML could be disrupted to combat this aggressive disease. The research delves into how JMJD1C facilitates leukemia cell survival by forming liquid-like condensates through its intrinsically disordered N-terminal region. This unique feature enables JMJD1C to be recruited by RUNX1 to genomic loci, including super-enhancers (SEs). These interactions activate key genes responsible for AML cell proliferation and metabolic processes, maintaining the leukemic state. Importantly, the study highlights that JMJD1C's non-catalytic functions are critical, with its condensate-forming ability being essential for RUNX1 recruitment and gene regulation. Key experiments revealed that disrupting JMJD1C's N-terminal region impairs its ability to form condensates and interact with RUNX1, leading to reduced leukemia cell viability. Moreover, JMJD1C's RUNX1-containing condensates might mediate enhancer-promoter interactions crucial for the expression of key leukemic genes regulated by RUNX1. These findings underscore the therapeutic potential of targeting the JMJD1C-RUNX1 axis to halt leukemia progression. Dr. Mo Chen, one of the senior authors of the study, highlighted the transformative potential of these findings: This research uncovers a previously unappreciated role for JMJD1C in leukemia biology. By elucidating its interaction with RUNX1, we can now envision therapeutic strategies that target this axis across diverse AML subtypes. The discovery of JMJD1C's role in AML cell survival opens a new frontier in leukemia treatment. By targeting the JMJD1C-RUNX1 interaction, researchers hope to disrupt the transcriptional programs sustaining leukemia cells, offering a universal strategy to tackle AML's heterogeneity. This approach holds promise for overcoming resistance to current therapies and improving patient outcomes. Future research will focus on translating these molecular insights into clinical interventions, heralding a new era in the fight against leukemia. DOI 10.1093/procel/pwae059 Original Source URL Funding information This work was funded by National Key R&D Program of China (grant 2021YFA1300100 to M.C.), Beijing Municipal Natural Science Foundation (grant JQ23024 to M. C.), Leukemia and Lymphoma Society (grant 7021-20 to R.G.R), National Natural Science Foundation of China (grant 32300445 to Q.C.) and a Tsinghua-Peking Center for Life Sciences postdoctoral fellowship to Q.C.. Lucy Wang BioDesign Research Legal Disclaimer:
