TFEB-mediated autophagy dysregulation links with PRPF31 deficiency-induced photoreceptor death via PLK4 downregulation.

Mutations in the pre-mRNA processing factor 31 gene (PRPF31) are a common cause of autosomal dominant retinitis pigmentosa (adRP), an inherited retinopathy characterized by progressive photoreceptor degeneration and vision loss. In a large Chinese adRP pedigree, we identified a PRPF31 c.544_618del mutation that causes a drastic reduction in protein expression via haploinsufficiency. We investigated its pathogenesis using a multi-model approach and found a core pathogenic axis wherein PRPF31 deficiency downregulates polo-like kinase 4 (PLK4), relieving its inhibition on transcription factor EB (TFEB). This triggers TFEB nuclear translocation and subsequent transcriptional upregulation of autophagy/lysosomal genes, driving autophagic hyperactivation. This autophagic hyperactivation, in turn, initiates a vicious cycle with severe mitochondrial dysfunction, characterized by structural abnormalities, respiratory deficits, adenosine triphosphate deficiency, and reactive oxygen species accumulation. Our work unveils a previously unrecognized pathophysiological mechanism for PRPF31-related retinopathy, by which PRPF31 deficiency drives a pathologic cascade between autophagy and mitochondria via the PLK4-TFEB axis, and provides crucial mechanistic insight and valuable models for developing interventional strategies targeting this pathway.