Biology subjects

Yi, W.

Publications and source records attributed to Yi, W..

3 recordsLinked to original sources

bioRxiv2018

The Landscape of Parkin Variants Reveals Pathogenic Mechanisms and Therapeutic Targets in PD

Mutations in Parkin (PARK2) are the most common genetic cause of early-onset Parkinsons disease (PD). Parkin encodes an E3 ubiquitin ligase implicated in the turnover of damaged mitochondria. Hundreds of Parkin missense variants have been reported in public databases, yet the role of most of them in PD remains unclear. We analyzed Parkin variants using clinical, experimental, and structural modeling approaches. For most variants, clinical evidence alone was insufficient to determine pathogenicity. Utilizing a cell model that allows measurement of Parkin-mediated mitophagy and Parkin stability, 51 variants were classified into five groups based on their effect on Parkin function. Most variants were like wildtype but, unexpectedly, several enhanced mitophagy. A minority destabilized Parkin or severely disrupted Parkin-mediated mitophagy, most of which were also determined as pathogenic based on clinical evidence alone. Structural simulation predicted discrete mechanisms explaining both increases and decreases in Parkin function. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally-occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. These findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets for genotype-specific drug design.

neuroscience↗

bioRxiv2018

Single-cell RNA-seq analysis maps the development of human fetal retina

Vision starts with image formation at the retina, which contains diverse neuronal cell types that extract, process, and relay visual information to higher order processing centers in the brain. Though there has been steady progress in defining retinal cell types, very little is known about retinal development in humans, which starts well before birth. In this study, we performed transcriptomic profiling of developing human fetal retina from gestational weeks 12 to 27 using single-cell RNA-seq (scRNA-seq) and used pseudotime analysis to reconstruct the developmental trajectories of retinogenesis. Our analysis reveals transcriptional programs driving differentiation down four different cell types and suggests that Muller glia (MG) can serve as embryonic progenitors in early retinal development. In addition, we also show that transcriptional differences separate retinal progenitor cells (RPCs) into distinct subtypes and use this information to reconstruct RPC developmental trajectories and cell fate. Our results support a hierarchical program of differentiation governing cell-type diversity in the developing human retina. In summary, our work details comprehensive molecular classification of retinal cells, reconstructs their relationships, and paves the way for future mechanistic studies on the impact of gene regulation upon human retinogenesis.

neuroscience↗

bioRxiv2018

(-)-Epigallocatechin-3-gallate inhibition of Epstein-Barr virus lytic replication involves latent membrane protein 1-mediated MAPK signaling pathways

AbstractEBV lytic replication has been shown to be important for carcinogenesis. Latent membrane protein 1 (LMP1) plays an important role in the viral latent infection and is abundantly expressed after EBV entry into the lytic cycle. However, the biological significance of LMP1 continuous expression in EBV lytic cycle is still not completely understood. We found that LMP1 promotes EBV reactivation by activating the downstream MAPK signaling in both AGS-EBV and B95.8 cells. In AGS-EBV cells, LMP1 induces EBV the initiation of the EBV lytic cycle in a p53 dependent manner. Activation of c-Jun by LMP1 through JNKs appears to be involved in EBV reactivation in p53 mutant B95.8 cells. We also demonstrated that EGCG, an anti-EBV agent, inhibits LMP1 expression and the activation of the downstream MAPK signaling pathways, followed by downregulation of EBV lytic protein expression level. Together, this study provides the first evidence that LMP1 promotes EBV reactivation via activation of the MAPK signaling pathways. Our findings further demonstrate that the mechanisms underlying EGCG inhibition of the EBV lytic replication involve the suppression of LMP1-mediated MAPK signaling pathways.\n\nSummary statementThis study definitely confirms the role of LMP1 in EBV reactivation and further explores the mechanism by which EGCG inhibits EBV lytic replication.

molecular biology↗