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Dihydroceramide desaturase modulates autolysosome maturation and ameliorates CRB1 retinopathy
Fei-Yang Tzou1, Pei-Huan Chuang2, Chia-Heng Hsu1
1Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Insights
Loss of CRB1 gene function causes retinal degeneration. Overactivating autophagy is implicated, but inhibiting it via dihydroceramide desaturase (ifc) ameliorates neurodegeneration in CRB1 retinopathy models.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Ophthalmology
Background:
- CRB1 gene variants are linked to retinitis pigmentosa (RP), a condition causing retinal degeneration and vision loss.
- Current treatments for CRB1-associated retinopathy are lacking.
- The roles of endolysosomal systems and autophagy in CRB1 retinopathy pathogenesis remain unclear.
Purpose of the Study:
- To investigate the disease mechanisms underlying CRB1 retinopathy.
- To explore the involvement of autophagy and endolysosomal pathways in CRB1 loss-of-function models.
Main Methods:
- Utilized Drosophila melanogaster loss-of-function mutants for the crumbs (crb) gene, the homolog of CRB1.
- Analyzed autophagic activity and expression of dihydroceramide desaturase (ifc).
- Investigated the mechanistic link between ifc, Rac1, Atg8, and autophagy, and tested the effects of autophagy inhibition on neurodegeneration.
Main Results:
- Loss of crb led to overactivated autophagy in Drosophila eyes.
- Dihydroceramide desaturase (ifc) was upregulated in crb mutants.
- Overexpression of ifc inhibited autolysosomes and autophagic cell death by enhancing Rac1-Atg8 binding, thereby inhibiting autophagy.
- Inhibition of autophagy through ifc, chloroquine, or Beclin-1 RNAi ameliorated neurodegeneration in crb mutant eyes.
Conclusions:
- Dihydroceramide desaturase plays a crucial role in modulating autolysosome function in the context of CRB1 loss-of-function.
- Targeting autophagy inhibition presents a potential therapeutic strategy for CRB1 retinopathy.
- These findings offer new insights into the pathogenesis of CRB1 retinopathy and potential treatment avenues.
Abstract:
Variants in the CRB1 gene cause retinal degeneration and subsequent vision impairment in patients of retinitis pigmentosa (RP). No treatments are currently available to cure or impede the progression of CRB1-associated retinopathy. Previous studies have revealed alterations in the endolysosomal systems and autophagy in the absence of CRB1, but their roles in the pathogenesis of CRB1 retinopathy are unclear. Here, we examined the disease mechanism of CRB1 retinopathy using loss-of-function mutants of crumbs (crb), the Drosophila homolog of CRB1. We found that the loss of crb results in overactivation of autophagy in the eye. We also discovered that dihydroceramide desaturase encoded by infertile crescent (ifc), was up-regulated in crb mutants. Overexpression of ifc inhibited autolysosomes and alleviated Atg1-induced autophagic cell death. Mechanistically, ifc enhanced the binding of Rac1 to Atg8 and increased the autophagosomal localization of active Rac1, thus inhibiting autophagy. Importantly, autophagy inhibitions achieved through ifc overexpression, chloroquine treatment, or Beclin-1 RNAi all ameliorated the neurodegeneration of crb mutant eyes. Together, these findings highlight the mechanism of dihydroceramide desaturase in modulating autolysosome functions in crb mutants, providing new insights for developing treatments against CRB1 retinopathy.
