Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models
Abstract
Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Biyue Zhu
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School
Zhenhua Liu
Shanghai Collaborative Innovation Center of Agri-Seeds, School of Agriculture and Biology, Shanghai Jiao Tong University
Richard Van
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma
Huizhe Wang
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School
Shi Kuang
State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology
Yuntao Jia
Department of Pharmacy, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents’ Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders
Erick Calderon Leon
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma
Fan Yang
Jing Zhang
Jun Yang
Howard Hong
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School
Fleur Lobo
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma
Astra Yu
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School
Johnson Wang
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School
Rudolph E. Tanzi
Can Zhang
School of Integrated Circuits and Electronics, MIIT Key Laboratory for Low-Dimensional Quantum Structure and Devices
Xiaobo Mao
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine
Yihan Shao
Department of Chemistry
Chongzhao Ran
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School