Biology subjects

Li, Z.-L.

Publications and source records attributed to Li, Z.-L..

4 recordsLinked to original sources

bioRxiv2025

Spatial Transcriptomics Reveal Developmental Dynamics of the Human Cerebral Cortex and Striatum

The human fetal brain undergoes morphological changes that contribute to the development of regional functionalities. However, the features of structural development, the underlying molecular and cellular signatures in the fetal brain remain unclear. With spatial transcriptomics and snRNA-seq, we identified 25 forebrain regions and characterized the dynamic changes in the cortex and striatum during the late first and early second trimesters. In particular, we discovered that temporal lobe enriched NPY-expressing L2/3 EX neuron potentially interacted with L4 EX neurons during cortical expansion and arealization. Additionally, the gyrus and sulcus were developmental asynchronous, in which HOPX and SPARC genes were potentially involved. Further investigation on the striatum showed specific genes and cell types that enriched in patch and matrix compartments, and SST-positive interneurons potentially involved in the development of these structures. Together, our results give insights into the understanding of early fetal brain development.

bioinformatics↗

bioRxiv2022

The tau oligomer antibody APNmAb005 detects early-stage pathological tau enriched at synapses and rescues neuronal loss in long-term treatments

Numerous tau immunotherapies are being developed against Alzheimers disease (AD), but it has been challenging to specifically target early-stage tau aggregates using conformation-dependent antibodies. Here, we report a monoclonal antibody, APNmAb005, that recognized a conformational epitope associated with tau oligomers. In AD brain extracts, mAb005 preferentially recognized oligomeric tau in the synapse over monomeric tau in the cytosol. In the prefrontal cortex and hippocampus, mAb005 immunoreactivity was strongly present in early-stage AD but surprisingly diminished in late-stage AD (Braak stage VI). mAb005 also recognized aggregates in 3R tauopathies (Picks disease) and 4R tauopathies (corticobasal degeneration and progressive supranuclear palsy), including those in astrocytes and oligodendrocytes. In rTg4510 mice (P301L tau), mAb005 immunoreactivity first appeared in distal neurites but much later in neuronal somas. Thus, the mAb005 epitope appears to be associated with early-stage oligomers of tau (esoTau) that accumulate around synapses in AD, which is also detectable in both 3R and 4R tauopathies. In cellular uptake models of tauopathy transmission, mAb005 blocked the formation of intracellular inclusions induced by incubation with rTg4510 mouse brain extracts. Long-term treatments with mAb005 in rTg4510 mice partially rescued synaptic and neuronal loss in the hippocampus without promoting overall tau clearance. Our data suggest that immunotherapies targeting esoTau enriched around synaptic sites may alleviate tau toxicity against synapses and neurons, which may be a promising treatment strategy against AD. One Sentence SummaryA tau-conformer antibody recognizing synaptic oligomers and 3R, 4R, and mixed aggregates in humans rescues neuronal loss in mouse tauopathy models.

neuroscience↗

bioRxiv2017

The RNA-binding site of poliovirus 3C protein doubles as a phosphoinositide-binding domain

Some viruses use phosphatidylinositol phosphate (PIP) to mark membranes used for genome replication or virion assembly. PIP-binding motifs of cellular proteins do not exist in viral proteins. Molecular-docking simulations revealed a putative site of PIP binding to poliovirus (PV) 3C protein that was validated using NMR spectroscopy. The PIP-binding site was located on a highly dynamic -helix that also functions in RNA binding. Broad PIP-binding activity was observed in solution using a fluorescence polarization assay or in the context of a lipid bilayer using an on-chip, fluorescence assay. All-atom molecular dynamics simulations of the 3C protein-membrane interface revealed PIP clustering and perhaps PIP-dependent conformations. PIP clustering was mediated by interaction with residues that interact with the RNA phosphodiester backbone. We conclude that 3C binding to membranes will be determined by PIP abundance. We suggest that the duality of function observed for 3C may extend to RNA-binding proteins of other viruses.

biochemistry↗

bioRxiv2017

Molecular Dynamics Simulations Of Membrane Deformation Induced By The Amphiphilic Helices Of Epsin, Sar1p And Arf1

The N-terminal amphiphilic helices of proteins Epsin, Sar1p and Arf1 play a critical role in initiating membrane deformation. We present here the study of the interactions of these amphiphilic helices with the lipid membranes by combining the all-atom and coarse-grained simulations. In the all-atom simulations, we find that the amphiphilic helices of Epsin and Sar1p have a shallower insertion depth into the membrane compared to the amphiphilic helix of Arf1, but remarkably, the amphiphilic helices of Epsin and Sar1p induce higher asymmetry in the lipid packing between the two monolayers of the membrane. The insertion depth of amphiphilic helix into the membrane is determined not only by the overall hydrophobicity but also by the specific distribution of polar and non-polar residues along the helix. To directly compare their ability of deforming the membrane, we further apply coarse-grained simulations to investigate the membranes deformation under the insertion of multiple helices. Importantly, it is found that the amphiphilic helices of Epsin and Sar1p generate a larger membrane curvature than that of Arf1, in accord with the experimental results qualitatively. These findings enhance our understanding of the molecular mechanism of the protein-driven membrane remodeling.

biophysics↗