Biology subjects

Labra, S. R.

Publications and source records attributed to Labra, S. R..

5 recordsLinked to original sources

bioRxiv2026

Autophagy activator AA-20 engages CDK5 to promote lipophagy and improve neurodegeneration-associated phenotypes

Lipophagy, the selective degradation of lipid droplets (LDs) by autophagy, has the potential to ameliorate neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD), wherein LD accumulation has been linked to the exacerbation of the proteinopathy component of neurodegeneration. Pharmacological lipophagy inducers remain scarce. We previously identified AA-20 as a novel autophagy activator that acts independently of mTORC1 inhibition, thereby providing a means of stimulating autophagy while avoiding the immunosuppressive side effects associated with direct mTORC1 inhibition. Prior work also showed that AA-20 treatment reduces PolyQ aggregate levels in several C. elegans tissues. Here, we demonstrate that AA-20 enhances LD recruitment to autophagosomes and promotes LD degradation via lysosomal acid lipase activation in murine hippocampal neuronal cells, consistent with lipophagy activation. In human Swedish Amyloid Precursor Protein mutated cerebral organoids, two weeks of AA-20 treatment normalized aberrant lipidomic profiles by selectively reducing various disease-associated lipids, while also correcting the AD-associated electrical hyperexcitability phenotype. Moreover, we identified cyclin-dependent kinase 5 (CDK5), a neuronal kinase linked to AD hyperexcitability and PD pathology, as a target of AA-20. AA-20-induced autophagy and lipid clearance in HT22 cells require CDK5. In a neuronal seeding model of -synuclein pathology, AA-20 reduced pS129--synuclein levels. Collectively, these findings indicate AA-20 can promote lipophagic clearance of LDs and mitigate multiple cellular phenotypes associated with lipidopathy and proteinopathy in neurodegenerative disease models.

molecular biology↗

bioRxiv2026

Molecular and Structural Characterization Reveals Divergent Extracellular Vesicle Profiles Between Wild Type and Alzheimer's Disease Cerebrocortical Organoids

Alzheimers disease (AD) is a neurodegenerative disorder affecting millions of patients globally. Despite significant efforts from researchers in recent decades, there are still many unanswered questions about AD pathogenesis. AD patient brains manifest changes in extracellular vesicles (EVs) secreted from diseased neurons, and the effect of this phenomenon remains poorly understood. EVs contain a variety of biomolecules and play a critical role in cell-to-cell communication in all eukaryotic organisms. Here, we report a thorough characterization of small EVs purified from cultures of human cerebrocortical organoids. These organoids are differentiated from human patient-derived stem cells that bear a familial AD mutation in the presenilin 1 (PSEN1) gene, or from an isogenic wildtype (WT) control. The organoid conditioned media was aspirated from cultures and processed for EV enrichment using a non-invasive technique that requires no cellular disruption. EVs purified from AD organoid conditioned media have a wider size distribution and show differential expression of tetraspanins CD63, CD9, and CD81 when compared to WT organoid-derived EVs. AD organoid-derived EVs can have single, double, and even triple membranes and display luminal fibrillar material. A deep proteomic profiling of the EVs reveals several statistically significant differences, including evidence for modifications in secretory autophagy. EV isolates from both WT and AD organoids show strong binding to amyloid detecting dyes, both in bulk fluorescence and fluorescence microscopy assays. After a 1-week co-culture of AD organoids with WT organoids, there is evidence of endosomal membrane transfer between the isogenic cultures with an increase in amyloid-{beta} peptides in the WT organoids. These observations support the notion that non-cell-autonomous spread of amyloid-containing EVs in human AD brains can be modeled in a cerebral organoid system.

neuroscience↗

bioRxiv2026

A strong start for sustained success: inclusivity through a national group mentorship program for first-year graduate students

In the United States, STEM graduate programs and workforce do not represent the demographics of the population. Obstacles, including a lack of transparency, community, and accessible information in navigating academia, disproportionately affect students from underserved backgrounds. Peer mentoring networks can address these disparities. Here, we describe Cientifico Latino, Inc.s Graduate Student Engagement and Community (CL-GSEC) program, a nationwide, group-based peer mentorship program that has served first-year graduate students across the U.S., especially those from underserved backgrounds. Surveys indicate CL-GSEC positively impacts the first-year graduate experience. We highlight key program features, challenges, and insights, such as financial strains faced by first-year graduate students. We offer suggestions for how faculty and departments can better support students during this critical early stage of graduate training. We hope that reporting on CL-GSECs program structure, evaluations, and findings will guide educational leaders in expanding programming for junior graduate students.

scientific communication and education↗

bioRxiv2025

Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids

Alzheimers disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimers disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1{Delta}E9/WT, PSEN1M146V/WT, or APPswe/WT. Our CO model reveals time-progressive accumulation of amyloid beta (A{beta}) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau species. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of A{beta} and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/661453v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@12ac9c6org.highwire.dtl.DTLVardef@24eceaorg.highwire.dtl.DTLVardef@3e3238org.highwire.dtl.DTLVardef@1530d1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Detecting boolean asymmetric relationships with a loop counting technique and its implications for analyzing heterogeneity within gene expression datasets

Many traditional methods for analyzing gene-gene relationships focus on positive and negative correlations, both of which are a kind of symmetric relationship. Biclustering is one such technique that typically searches for subsets of genes exhibiting correlated expression among a subset of samples. However, genes can also exhibit asymmetric relationships, such as if-then relationships used in boolean circuits. In this paper we develop a very general method that can be used to detect biclusters within gene-expression data that involve subsets of genes which are enriched for these boolean-asymmetric relationships (BARs). These BAR-biclusters can correspond to heterogeneity that is driven by asymmetric gene-gene interactions, e.g., reflecting regulatory effects of one gene on another, rather than more standard symmetric interactions. Unlike typical approaches that search for BARs across the entire population, BAR-biclusters can detect asymmetric interactions that only occur among a subset of samples. We apply our method to a single-cell RNA-sequencing data-set, demonstrating that the statistically-significant BAR-biclusters indeed contain additional information not present within the more traditional boolean-symmetric-biclusters. For example, the BAR-biclusters involve different subsets of cells, and highlight different gene-pathways within the data-set. Moreover, by combining the boolean-asymmetric- and boolean-symmetric-signals, one can build linear classifiers which outperform those built using only traditional boolean-symmetric signals.

bioinformatics↗