Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models

Protein misfolding is a crucial pathological phenomenon driving neurodegenerative diseases that affect millions of people. Visualizing misfolded proteins would greatly facilitate early diagnosis, etiology elucidation, and therapy monitoring of neurodegeneration. Although several probes have been reported, versatile and sensitive detection in vivo is still challenging. We demonstrated that both generic and precise detection of misfolded proteins could be achieved with a chemiluminescence probe, ADLumin-1. For generic aspect, ADLumin-1 was highly sensitive to various misfolded proteins, showing up to 127.73-fold higher signal-to-noise ratio than gold standard dye of Thioflavin T. ADLumin-1 could also non-invasively visualize misfolded proteins in mouse models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. For precise aspects, ADLumin-1 can selectively detect α-synuclein in CSF at the femtomolar level by combining with protein misfolding cyclic amplification technology in vitro. In addition, ADLumin-1 enables selective in vivo imaging of misfolded α-synuclein in transgenic mice models by employing bioorthogonal chemiluminescence resonance energy transfer strategy. Combining generality and precision, our findings could be widely applied in preclinical and clinical studies of neurodegenerative diseases.