ABSTRACT Over 40 amyloidogenic proteins have been identified to cause amyloidosis diseases in clinics. Tissue deposition of amyloid proteins entangled with interacting partners is a characteristic pathological hallmark of amyloidosis diseases. However, the proteomic complexity of co‐aggregated amyloid deposits poses a clinical challenge to diagnose the exact disease‐causing pathogenic proteins in patients’ biopsied tissue. Herein, we present a photocatalytic proteomic method, named Amyloid‐ID, as a promising approach to identify the composition of amyloid deposits for clinical proteotyping of amyloidosis diseases. Amyloid‐ID is enabled by a photosensitized probe analogous to a pan‐amyloid sensor, Thioflavin T. We show this probe photocatalyzes protein labeling via reactive oxygen species and demonstrate its applicability in both AD mouse models and human laryngeal samples. Next, we exemplify its utility by proteotyping the pathogenic protein underlying the rare laryngeal amyloidosis (LA). Using patients’ biopsied tissue sections, we label, enrich, and profile the amyloid deposits. Proteomics analysis top‐ranks fibrinogen as a potential pathogenic protein. Biochemical and biophysical characterizations confirm that fibrinogen can aggregate into amyloid fibrils. Intriguingly, we observe that fibrinogen's fibrillation is sensitive to mechanical forces, particularly impacted by sonication. Such observation coincides with its primary larynx deposition, where frequent vocal cord friction occurs. Overall, given the photocatalytic properties, our Amyloid‐ID serves as a promising clinical proteotyping method for amyloidosis diseases.
Feng et al. (2026) studied this question.