APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to lipogenesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride after fatty acid pulse-chase. This LD size phenotype was rescued by chimeric APOE that targets only LDs. Like APOE depletion, APOE4-expressing astrocytes form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 causes aberrant LD composition and morphology. Our study contributes to accumulating evidence that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation, which could contribute to Alzheimer's disease risk.

The cell biology of APOE in the brain.

Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes.

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to neutral lipid synthesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the ER lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs containing more unsaturated triglyceride. This LD size distribution phenotype was rescued by chimeric APOE that targets only LDs. APOE4 - expressing astrocytes also form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the larger LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 is a toxic gain of function variant that causes aberrant LD composition and morphology. We propose that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation or lipotoxicity, which could contribute to Alzheimer's disease risk. Summary: Windham et al . discover that APOE in astrocytes can traffic to lipid droplets (LDs), where it modulates LD composition and size. Astrocytes expressing the Alzheimer's risk variant APOE4 form large LDs with impaired turnover and increased peroxidation sensitivity.

Lipid droplets go through a (liquid crystalline) phase.

Lipid droplets (LDs) are key organelles for fat storage and trafficking. In this issue, Rogers et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202205053) show that glucose restriction triggers liquid crystalline lattice formation within LDs, which in turn alters the recruitment of proteins to the LD surface.

Nuclear movement in growing Arabidopsis root hairs involves both actin filaments and microtubules.

Nuclear migration during growth and development is a conserved phenomenon among many eukaryotic species. In Arabidopsis, movement of the nucleus is important for root hair growth, but the detailed mechanism behind this movement is not well known. Previous studies in different cell types have reported that the myosin XI-I motor protein is responsible for this nuclear movement by attaching to the nuclear transmembrane protein complex WIT1/WIT2. Here, we analyzed nuclear movement in growing root hairs of wild-type, myosin xi-i, and wit1 wit2 Arabidopsis lines in the presence of actin and microtubule-disrupting inhibitors to determine the individual effects of actin filaments and microtubules on nuclear movement. We discovered that forward nuclear movement during root hair growth can occur in the absence of myosin XI-I, suggesting the presence of an alternative actin-based mechanism that mediates rapid nuclear displacements. By quantifying nuclear movements with high temporal resolution during the initial phase of inhibitor treatment, we determined that microtubules work to dampen erratic nuclear movements during root hair growth. We also observed microtubule-dependent backwards nuclear movement when actin filaments were impaired in the absence of myosin XI-I, indicating the presence of complex interactions between the cytoskeletal arrays during nuclear movements in growing root hairs.

A Circle RNA Regulatory Axis Promotes Lung Squamous Metastasis via CDR1-Mediated Regulation of Golgi Trafficking.

Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5p more potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and coatomer protein I (COPI) proteins, no longer promoted migration upon blockade of Golgi trafficking. Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo. This report demonstrates a novel role for CDR1 in promoting metastasis and Golgi trafficking. These findings reveal an miRNA/circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. SIGNIFICANCE: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1.