Supramolecular Probe for Monitoring Lysosomal Ferritinophagy to Facilitate the Early Diagnosis of Parkinson's Disease

Abstract

Lysosomal iron overload, resulting from dysregulated ferritinophagy, is a significant early event in the progression of Parkinson's disease (PD). This condition causes iron accumulation within cells, triggering oxidative stress and ferroptosis, along with mitochondrial dysfunction and α-synuclein (α-syn) aggregation, ultimately damaging dopaminergic neurons irreversibly. However, tools for real-time monitoring of Fe³⁺ dynamics in vivo are limited. In this study, we introduce TPE-4B/4Q[7], a supramolecular fluorescent probe designed for selective and stable tracking of Fe³⁺ changes within lysosomes. This probe exhibits excellent photostability, low cytotoxicity, and a detection limit of 1.23 × 10⁻⁶ M. In cellular models of PD, TPE-4B/4Q[7] effectively monitors lysosomal ferritinophagy-induced Fe³⁺ overload, allowing for the assessment of oxidative stress, mitochondrial function, and the levels of key biomarkers such as α-syn and tyrosine hydroxylase. Additionally, this probe can track iron accumulation linked to neurodegenerative lesions in Caenorhabditis elegans and MPTP-induced PD mouse models, with signal changes correlating closely with neurodegenerative phenotypes and molecular pathology. Notably, TPE-4B/4Q[7] enables non-invasive brain imaging via nasal delivery. TPE-4B/4Q[7] is a sensitive molecular indicator for early risk assessment and monitoring of PD progression. It is anticipated to be an effective instrument for the early diagnosis of PD.