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

Area of Science:

• Genetics and Molecular Biology
• Ophthalmology
• Cellular Biology

Background:

• Mutations in the pre-mRNA processing factor 31 (PRPF31) gene are a primary cause of autosomal dominant retinitis pigmentosa (adRP).
• adRP is an inherited condition leading to progressive photoreceptor cell degeneration and vision impairment.

Purpose of the Study:

• To elucidate the pathogenic mechanism of a specific PRPF31 mutation (c.544_618del) identified in a Chinese adRP family.
• To investigate the molecular pathway linking PRPF31 deficiency to photoreceptor degeneration.

Main Methods:

• A multi-model approach was employed to study the identified PRPF31 mutation.
• Analysis included assessing protein expression, gene regulation, and cellular processes like autophagy and mitochondrial function.

Main Results:

• The PRPF31 c.544_618del mutation results in haploinsufficiency and reduced PRPF31 protein levels.
• PRPF31 deficiency was found to downregulate polo-like kinase 4 (PLK4), which in turn disinhibits transcription factor EB (TFEB).
• This cascade leads to TFEB nuclear translocation, upregulation of autophagy/lysosomal genes, hyperautophagy, and severe mitochondrial dysfunction.

Conclusions:

• PRPF31 deficiency initiates a pathogenic cascade involving the PLK4-TFEB axis, linking dysregulated autophagy and mitochondrial dysfunction in adRP.
• This study reveals a novel mechanism for PRPF31-related retinopathy.
• The findings provide valuable insights and models for developing therapeutic interventions targeting this pathway.