Biology subjects

Luo, Z.-G.

Publications and source records attributed to Luo, Z.-G..

4 recordsLinked to original sources

bioRxiv2026

Hopx expression marks Aβ clearance astrocytes in Alzheimers disease

SUMMERYAstrocytic dysfunction is closely associated with nearly all types of neurological diseases. Targeting astrocyte regulation has thus emerged as an important potential therapeutic strategy for neurological disorders. However, mechanisms that induce astrocyte dysfunction under pathological conditions have not been fully elucidated. In this study, we identified that Homeodomain-only protein X (Hopx) is downregulated in astrocytes across inflammatory models, Alzheimers disease (AD) mouse models, and brain tissues from AD patients. In the brains of AD mice, Hopx-positive astrocytes exhibit efficient {beta}-amyloid (A{beta}) plaque clearance, while knockout of Hopx leads to astrocytic dysfunction. Conversely, astrocyte-specific overexpression of Hopx not only significantly enhances their A{beta} phagocytic function but also effectively reduces the generation of neurotoxic astrocytes while increasing protective astrocytes. In summary, this study demonstrates the core regulatory mechanism underlying astrocytic dysfunction under AD pathological conditions and provides important potential targets for developing therapeutic strategies for AD by targeting astrocyte regulatory pathways.

neuroscience↗

bioRxiv2026

Joint Segmental Duplication Co-option Drives Human-specific Transcriptional Readthrough and Expression Fine-tuning of NPEPPS-TBC1D3

Segmental duplication (SD) is a major driver of functional changes in evolution and disease. Many genes embedded within SDs, such as NPEPPS and TBC1D3, display substantial copy number variation (CNV) across individuals. Yet, the precise identification of the functional copies and their transcriptional outputs remains largely unstudied. Focusing on NPEPPS and TBC1D3, we illustrate human-specific expression fine-tuning mechanisms associated with readthrough transcripts. We identified a human-specific NPEPPS-TBC1D3 digenic genomic structure that originated from a joint SD pair and became fixed across populations. Experiments demonstrate that this structure generates NPEPPS-TBC1D3 readthrough transcripts, which are the predominant isoforms of TBC1D3 expression in various cell types, fine-tuning its protein level. Furthermore, a human-specific hypomethylation signal within an upstream CpG island of NPEPPS precisely pinpoints the expressed TBC1D3 paralog. Moreover, we reveal transcriptional readthrough events are [~]3-fold enriched for joint-SD-associated transcriptional readthrough (JSDTR) and identify 109 JSDTR gene pairs, including neurodevelopmentally important pairs and clinically interesting SERF1A/B-SMN1/2. Taken together, our findings comprehensively describe an example of how a joint SD event shaped evolution and suggest that JSDTR is a broad mechanism for the emergence of new functions.

genetics↗

bioRxiv2022

Generation of Vascularized Brain Organoids to Study Neurovascular Interactions

The recently developed brain organoids have been used to recapitulate the processes of brain development and related diseases. However, the lack of vasculatures, which regulate neurogenesis, brain disorders, and aging process, limits the utility of brain organoids. In this study, we induced vessel and brain organoids respectively, and then fused two types of organoids together to obtain vascularized brain organoids. The fused brain organoids were engrafted with robust vascular network-like structures, and exhibited increased number of neural progenitors, in line with the possibility that vessels regulate neural development. Fusion organoids also contained functional blood-brain-barrier (BBB)-like structures, as well as microglial cells, a specific population of immune cells in the brain. The incorporated microglia responded actively to immune stimuli to the fused brain organoids. Thus, the fusion organoids established in this study allow modeling interactions between the neuronal and non-neuronal components in vitro, in particular the vasculature and microglia niche.

developmental biology↗

bioRxiv2021

High-throughput mapping of single-cell molecular and projection architecture of neurons by retrograde barcoded labelling

Deciphering patterns of connectivity between neurons in the brain is a critical step toward understanding brain function. Imaging-based neuroanatomical tracing identifies area-to-area or sparse neuron-to-neuron connectivity patterns, but with limited throughput. Barcode-based connectomics maps large numbers of single-neuron projections, but remains a challenge for jointly analyzing single-cell transcriptomics. Here, we established a rAAV2-retro barcode-based multiplexed tracing method that simultaneously characterizes the projectome and transcriptome at the single neuron level. We uncovered dedicated and collateral projection patterns of ventromedial prefrontal cortex (vmPFC) neurons to five downstream targets and found that projection-defined vmPFC neurons are molecularly heterogeneous. We identified transcriptional signatures of projection-specific vmPFC neurons, and verified Pou3f1 as a marker gene of neurons extending collateral branches to dorsomedial striatum and lateral hypothalamus. In summary, we have developed a new multiplexed technique whose paired connectome and gene expression data can help reveal organizational principles that form neural circuits and process information.

neuroscience↗