Catalytic function of zinc finger proteins against amyloid- amyloidogenesis

Zinc finger (ZF) proteins are integral to neurological processes by mediating biomolecular interactions and regulating gene expression. Despite their implication in neurodegenerative diseases, the precise contribution of ZF proteins to disease pathology remains unclear. Here we show the direct binding of the ZF protein PARIS(ZF2–4) with amyloid-beta (Abeta) as well as its catalytic function in reprofiling Abeta aggregation and cytotoxicity, a key contributor to Alzheimer’s disease. The complex formation between PARIS(ZF2–4) and Abeta promotes the amorphous aggregation of Abeta, which reduces its interaction with cell membranes and prevents the formation of toxic oligomers and fibrils, thus alleviating A-induced cytotoxicity. Through sequence-based reactivity and mechanistic analyses employing fragments and variants, we identify structural motifs critical for PARIS(ZF2–4)’s function. These findings demonstrate a novel modulative role of ZF proteins in Abeta amyloidogenesis, highlighting a sequence–reactivity relationship that offers insights into potential therapeutic avenues for neurodegenerative disorders.