Abstract
SignificanceThe pathological misfolding of proteins is a central event in neurodegenerative diseases. However, developing specific optical probes for each misfolded protein remains challenging, limiting both sensitive detection in biofluids and noninvasive imaging in vivo. We introduce a dual-mode chemiluminescence strategy that overcomes these limitations by enabling both generic and specific detection of misfolded proteins on a single probe platform. This approach achieves sensitive detection of various misfolded proteins and enables noninvasive imaging across multiple disease models in vivo. Furthermore, it allows femtomolar-level detection of α-synuclein in biofluids and supports longitudinal tracking of α-synuclein progression in Parkinson’s disease mouse models. This versatile approach provides a powerful and practical tool to advance etiological studies and early diagnosis of neurodegenerative disorders.
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.