Biology subjects

Banik, P.

Publications and source records attributed to Banik, P..

3 recordsLinked to original sources

bioRxiv2025

PRPF8-associated retinitis pigmentosa variant induces human neural retina-autonomous photoreceptor defects

Retinitis pigmentosa (RP) is an inherited retinal disorder characterized by the progressive loss of photoreceptors that currently lacks effective treatment. Here, we investigated the impact of the pathogenic PRPF8-Y2334N variant on neural retina cells in hiPSC-derived retinal organoids. Expression of this variant resulted in photoreceptor defects, including thinning of the outer segment layer. At the molecular level, we observed relatively minor changes in mRNA expression in multiple retinal cells, indicating that neural retina cells are impacted independently of retinal pigment epithelium (RPE). We found splicing alterations in genes associated with neural and retinal diseases, including those involved in intraflagellar transport, suggesting that these genes may represent common targets of splicing factor mutations. We further detected the misexpression of several circular RNAs (circRNAs), which could serve as early biomarkers of splicing defects caused by RP mutations. Together, we present a model of RP that recapitulates photoreceptor degeneration and demonstrates that these defects are independent of RPE erosion.

cell biology↗

bioRxiv2023

Nuclear quality control of non-imported secretory proteins attenuates proteostasis decline in the cytosol

Mistargeting of secretory proteins to the cytosol can induce formation of aggregation-prone conformers and subsequent proteostasis decline. We have identified a quality control pathway that redirects non-ER-imported prion protein (PrP) to proteasomal degradation in the nucleus to prevent formation of toxic aggregates in the cytosol. Upon aborted ER import, PrP sequentially interacted with VCP/p97 and importins, which kept PrP soluble and promoted its nuclear import. In the nucleus, RNA buffered aggregation of PrP to facilitate ubiquitin-dependent proteasomal degradation. Notably, the cytosolic interaction of PrP with VCP/p97 and its nuclear import were independent of ubiquitination but required the intrinsically unstructured N-terminal domain of PrP. Transient proteotoxic stress promoted the formation of self-perpetuating PrP aggregates in the cytosol, which disrupted further nuclear targeting of PrP and compromised cellular proteostasis. Our study delineates a VCP/p97-dependent nucleus-based quality control pathway of non-ER-imported secretory proteins and emphasizes the important role of the nuclear milieu for the degradation of aggregation-prone proteins.

cell biology↗

bioRxiv2022

Retinitis pigmentosa associated mutations in mouse Prpf8 cause misexpression of circRNAs and degeneration of cerebellar granule neurons

A subset of patients suffering from a familial retinitis pigmentosa (RP) carry mutations in several spliceosomal components including PRPF8 protein. Here, we established two novel alleles of murine Prpf8 that genocopy or mimic aberrant PRPF8 found in RP patients - the substitution p.Tyr2334Asn and an extended protein variant p.Glu2331ValfsX15. Homozygous mice expressing either of the aberrant Prpf8 variants developed within first 2 months progressive atrophy of the cerebellum due to extensive granule neuron loss. Comparison of transcriptome from pre-degenerative and degenerative tissues revealed a subset of circRNAs that were deregulated in all tissues and both Prpf8-RP mouse strains. To identify potential risk factors that sensitize cerebellum for Prpf8 mutations we monitored expression of several splicing proteins during first eight weeks. We observed downregulation of all selected splicing proteins in wild-type cerebellum, which coincided with neurodegeneration onset. The decrease in splicing protein expression was further pronounced in mouse strains expressing mutated Prpf8. Collectively, we propose a model where physiological reduction of spliceosomal components during postnatal tissue maturation sensitizes cells to expression of aberrant Prpf8 and the subsequent deregulation of circRNAs triggers neuron death.

neuroscience↗