Biology subjects

Alper, S. L.

Publications and source records attributed to Alper, S. L..

4 recordsLinked to original sources

bioRxiv2026

An integrated multi-omic atlas of the choroid plexus highlights conserved molecular programs of epithelial function

The choroid plexus (ChP) is a specialized epithelial tissue responsible for production of cerebrospinal fluid (CSF), maintenance of the blood-CSF barrier and regulation of CSF-borne signaling factors. However, despite the ChP's central role in CSF homeostasis, conserved molecular programs of ChP epithelial function across species and conditions remain incompletely defined. In this study, we integrated eight mouse and human single-cell/nucleus RNA-seq datasets to build a multi-species ChP atlas capturing major epithelial, stromal, vascular, and immune populations. Cross-dataset differential expression identified a conserved epithelial gene program encompassing ion transport, barrier function, ciliogenesis, and secretory signaling, while prioritizing understudied genes including CLIC6 and VAT1L. Co-expression network analysis resolved conserved epithelial meta-programs, and transcription factor regulatory inference identified OTX2, MSX1, and GLIS3 among conserved regulators of epithelial gene expression. We also generated a novel Visium HD spatial transcriptomic atlas of mouse fourth-ventricle ChP to orthogonally validate epithelial modules. Lastly, cross-tissue analyses revealed substantial transcriptional overlap between ChP and retinal pigment epithelium, including shared epithelial genes and OTX2-associated regulatory relationships. Together, these findings define conserved molecular programs of ChP epithelial specialization, nominate candidate regulators for functional investigation, and provide an integrated cross-species and spatial resource for studying ChP physiology.

neuroscience↗

bioRxiv2026

A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies

Severe proteinopathies--such as retinitis pigmentosa, a form of inherited blindness--are driven by genetic mutations that overwhelm the quality control of the post-endoplasmic reticulum (post-ER) secretory pathway, causing toxic protein accumulation. Here, we identify a therapeutic node defined by a hetero-oligomeric cargo receptor complex consisting of TMED7, 2, 9, and 10. This "entrapment complex" anchors structurally and functionally diverse mutant clients within the early secretory pathway via TMED7 binding to the integral Golgi protein GRASP55. Disruption of the entrapment complex results in the clearance of accumulated protein cargoes. In vivo ablation of the entrapment node via inducible genetic deletion or via the small molecule BRD7635 reverses histopathological hallmarks and rescues functional deficits in clinically distinct proteinopathies of the kidney and the eye, including mitigating vision loss in a mouse model of retinitis pigmentosa.

cell biology↗

bioRxiv2024

Activation of PIEZO1 Inhibits Kidney Cystogenesis

The disruption of calcium signaling associated with polycystin deficiency has been proposed as the primary event underlying the increased abnormally patterned epithelial cell growth characteristic of Polycystic Kidney Disease. Calcium can be regulated through mechanotransduction, and the mechanosensitive cation channel Piezo1 has been implicated in sensing of intrarenal pressure and in urinary osmoregulation. However, a possible role for PIEZO1 in kidney cystogenesis remains undefined. We hypothesized that cystogenesis in ADPKD reflects altered mechanotransduction, suggesting activation of mechanosensitive cation channels as a therapeutic strategy for ADPKD. Here, we show that Yoda-1 activation of PIEZO1 increases intracellular Ca2+ and reduces forskolin-induced cAMP levels in mIMCD3 cells. Yoda-1 reduced forskolin-induced IMCD cyst surface area in vitro and in mouse metanephros ex vivo in a dose-dependent manner. Knockout of polycystin-2 dampened the efficacy of PIEZO1 activation in reducing both cAMP levels and cyst surface area in IMCD3 cells. However, collecting duct-specific Piezo1 knockout neither induced cystogenesis in wild-type mice nor affected cystogenesis in the Pkd1RC/RC model of ADPKD. Our study suggests that polycystin-2 and PIEZO1 play a role in mechanotransduction during cystogenesis in vitro, and ex vivo, but that in vivo cyst expansion may require inactivation or repression of additional suppressors of cystogenesis and/or growth. Our study provides a preliminary proof of concept for PIEZO1 activation as a possible component of combination chemotherapy to retard or halt cystogenesis and/or cyst growth.

cell biology↗

bioRxiv2020

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

cell biology↗