Biology subjects

Lehmann, K. S.

Publications and source records attributed to Lehmann, K. S..

4 recordsLinked to original sources

bioRxiv2024

Structural basis of bulk lipid transfer by bridge-like lipid transfer protein LPD-3

Bridge-like lipid transport proteins (BLTPs) are an evolutionarily conserved family of proteins that localize to membrane contact sites and are thought to mediate the bulk transfer of lipids from a donor membrane, typically the endoplasmic reticulum (ER), to an acceptor membrane, such as a that of the cell or an organelle 1. Despite the fundamental importance of BLTPs for cellular function, the architecture, composition, and lipid transfer mechanisms remain poorly characterized. Here, we present the subunit composition and the cryo-electron microscopy structure of the native LPD-3 BLTP complex isolated from transgenic C. elegans. LPD-3 folds into an elongated, rod-shaped tunnel whose interior is filled with ordered lipid molecules that are coordinated by a track of ionizable residues that line one side of the tunnel. LPD-3 forms a complex with two previously uncharacterized proteins, here named "Intake" and "Spigot", both of which interact with the N-terminal end of LPD-3 where lipids enter the tunnel. Intake has three transmembrane helices, one of which borders the entrance to the tunnel; Spigot has one transmembrane helix and extends 80 [A] along the cytosolic surface of LPD-3. Experiments in multiple model systems indicate that Spigot plays a conserved role in ER-PM contact site formation. Our LPD-3 complex structural data, together with molecular dynamics simulations of the transmembrane region in a lipid bilayer, reveal protein-lipid interactions that suggest a model for how the native LPD-3-complex mediates bulk lipid transport and provide a foundation for mechanistic studies of BLTPs.

biochemistry↗

bioRxiv2023

Astrocyte-dependent local neurite pruning and Hox gene-mediated cell death in Beat-Va neurons

Neuronal remodeling is extensive and mechanistically diverse across the nervous systems of complex metazoans. To explore circuit refinement mechanisms, we screened for new neuronal subtypes in the Drosophila nervous system that undergo remodeling early in metamorphosis. We find Beat-VaM neurons elaborate a highly branched neurite network during larval stages that undergoes local neurite pruning during early metamorphosis. Surprisingly, Beat-VaM neurons remodel their branches despite blockade of steroid hormone signaling and instead depend on signaling from astrocytes to activate pruning. We show Beat-VaL neurons undergo steroid hormone-dependent cell death in posterior but not anterior abdominal segments. Correct activation of apoptotic cell death relies on segment-specific expression of the hox gene Abd-B, which is capable of activating cell death in any Beat-VaL neuron. Our work provides new model cells in which to study neuronal remodeling, highlights an important role for astrocytes in activating local pruning in Drosophila independent of steroid signaling, and defines a Hox gene-mediated mechanism for segment-specific cell elimination. SummaryLehmann et al. characterize two new populations of neurons that undergo remodeling during Drosophila metamorphosis. Beat-VaM neurons undergo drastic neurite pruning that is largely independent of ecdysone signaling and instead is driven by astrocytes. Beat-VaL neurons undergo Abd-B mediated, caspase driven cell death in a segmentally restricted manner.

neuroscience↗

bioRxiv2018

Complement 3 signaling is necessary for the developmental refinement of olfactory bulb circuitry

The olfactory system depends upon organizational maps that are developmentally refined and maintained, however the cellular and molecular mechanisms that underlie these processes are unknown. Studies have shown that microglia and complement molecules are important for the developmental refinement of circuitry within the visual system, thus we asked whether they played a similar role in the olfactory system through the formation of the olfactory bulb (OB) maps, the glomerular and intrabulbar maps. Our findings revealed that microglia in mature animals engulf olfactory sensory neuron (OSN) axons and the synaptic terminals of tufted cells in the glomerular and intrabulbar maps respectively, suggesting microglia could anatomically shape the mature OB circuitry. To determine the mechanisms underlying this axonal pruning activity we used complement 3 (C3) and complement receptor 3 (CR3) knockout mice to investigate if C3 signaling was necessary for precise OB map development. Our results demonstrate that glomerular and intrabulbar map disorganization as typically present in early postnatal mice persists into adulthood when C3 signaling is disrupted. These data clearly establish the C3/CR3 pathway as necessary for the proper developmental refinement of both olfactory maps. We further present the olfactory system as a unique platform to study the role of glia in the development and adult refinement of regenerating circuits.

neuroscience↗

bioRxiv2018

Electron Microscopy Analysis of hAPP-Induced Neurodegeneration in the Glomerular Network

Loss of smell is an early indicator of Alzheimers disease (AD), making the olfactory system an accessible model to study the effect of AD related proteins such as Amyloid Precursor Protein (APP). The regenerative capacity of the system further enables studies of circuit recovery after APP-induced degeneration. While the cellular effects of APP are well documented, little is known about its effects on brain circuits at the ultrastructural level. To study circuitry changes, we overexpressed humanized APP with familial AD mutations (hAPP) in olfactory sensory neurons and performed serial electron microscopy on olfactory bulb glomeruli from both control and hAPP expressing mice. We found that hAPP-expressing mice showed a striking decrease in glomerular connectivity along with widespread changes of subcellular structures. By then turning off hAPP expression for 6 weeks we tested the capacity of glomerular circuits to recover and found clear restoration of both connectivity and subcellular features, including an increase in post-synaptic density to above the control level. These data provide an important ultrastructural view of olfactory regions associated with AD and suggest that circuit recovery is possible in brain tissue that has experienced APP-induced neurodegeneration.

neuroscience↗