bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–05–15
thirteen papers selected by
Rich Giadone, Harvard University
  1. Endoplasmic reticulum-associated, aggregation-prone protein substrates inform protein disaggregation in mammalian cell systems.
  2. Contribution of the Golgi and Endosomes to Proteostasis During Aging in the Nematode Caenorhabditis elegans.
  3. Optimization of a Chaperone Protein Disaggregase Complex for Neurodegenerative Disease.
  4. Folding state as the Decision Maker in Detecting Misfolded Proteins by Hsp70.
  5. A SUMO-dependent Pathway for Cytosolic Protein Quality Control.
  6. Protein Folding and Molecular Basis of Memory.
  7. SUMO1 Modification of Tau in Progressive Supranuclear Palsy.
  8. The Role of Heat Shock Proteins in Amyloid Body Reversal.
  9. Enzymes degraded under high light maintain proteostasis by transcriptional regulation in Arabidopsis.
  10. Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17.
  11. The degradation of misfolded proteins in the ER.
  12. Effects of Aging on Proteome Dynamics in Mice Brain Microvessels: ROS Scavengers, mRNA/Protein Stability, Glycolytic Enzymes, Mitochondrial Complexes, and Basement Membrane Components.
  13. Brain endothelial cell barrier function is compromised by autophagy depletion.
  1. FASEB J. 2022 May;36 Suppl 1
    Endoplasmic reticulum-associated, aggregation-prone protein substrates inform protein disaggregation in mammalian cell systems.
    Grant J Daskivich, Jeffrey L Brodsky.
      Neurodegenerative diseases afflict over 5 million Americans and are caused primarily by proteins and protein aggregates that disrupt proteostasis; the process which maintains protein function and quality control in the cell. Healthy cells can process small aggregates through the action of molecular chaperone assemblies and protein degradation pathways. However, highly stable aggregates irreversibly disrupt proteostasis and trigger disease onset. In contrast to human cells, the chaperone Hsp104 can resolve highly stable aggregates in yeast. Problematically, humans lack Hsp104. Therefore, we hypothesize that metazoan cells have developed alternative machinery to resolve stable protein aggregates. To address this hypothesis, we developed multiple endoplasmic reticulum (ER) localized substrates that have aggregation-prone cytosolic motifs. Substrates were comprised of either yeast or mammalian protein-derived membrane anchors and aggregation-prone and amyloid-like motifs. Because of their structure, we hypothesized that these substrates were dependent on ER associated degradation (ERAD) and became insoluble under stress conditions. We evaluated these substrates in HEK293H cells with cycloheximide chase and detergent fractionation assays and discovered each substrate largely depended on the proteasome for degradation while only some were insoluble at elevated temperatures. We then used biotin proximity labeling to identify potential protein chaperones associated with our substrates.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R3964
  2. FASEB J. 2022 May;36 Suppl 1
    Contribution of the Golgi and Endosomes to Proteostasis During Aging in the Nematode Caenorhabditis elegans.
    Morgan Palumbo, Christopher Saladino, Matthew Youngman.
      A gradual breakdown in the cellular networks that assure protein stability, termed proteostasis, contributes significantly to the accumulation of misfolded and aggregated proteins that severely compromises cellular function later in life. A progressive decline in the efficiency of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) causes cells to become particularly susceptible to disturbances affecting the biogenesis, folding, stability, and turnover of membrane proteins. While the dynamics of ER stress response mechanisms during aging have been well-characterized, less is understood about how the function of other organelles important for membrane protein biogenesis and turnover might change over time. We hypothesized that age-dependent changes in the function of the Golgi and endosomes could contribute to the collapse in proteostasis during adulthood. Using a reverse genetic approach in Caenorhabditis elegans, we probed the function of these two compartments by knocking down the expression of cogc-2, a member of the Conserved Oligomeric Golgi (COG) complex and of rme-8, encoding an endosomal protein important for the retrieval of Golgi residents and the recycling of plasma membrane proteins. A key component of the C. elegans innate immune response is the secretion of immune effector proteins into the intestinal lumen, which can itself trigger the ER stress response due to the increased flux through the secretory pathway. Therefore, as a proxy for the integrity of vesicular transport pathways we measured the survival of juvenile and adult animals infected with the bacterial pathogen Pseudomonas aeruginosa following RNAi treatments targeting cogc-2 or rme-8. While there was a negligible effect on late larval stage animals, reduced expression of cogc-2 and rme-8 enhanced the sensitivity of post-reproductive adult animals to infection. This suggests that components of vesicular transport pathways downstream of the ER could also contribute to proteostasis in an age-dependent manner through their roles in ensuring the proper localization of membrane proteins. Follow-up studies will use in vivo fluorescent reporters of protein stability to determine whether interfering with protein transport through the Golgi and endosomes accelerates the decline in proteostasis in older animals. Our studies imply that organelles involved in late steps of membrane protein biogenesis and stability play increasingly important roles in maintaining the proteome during aging.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.L7998
  3. FASEB J. 2022 May;36 Suppl 1
    Optimization of a Chaperone Protein Disaggregase Complex for Neurodegenerative Disease.
    Evan Qiang, Erica Gorenberg, Eddie Chuang, Gabriel Braun, James Shorter.
      Toxic and pathologic protein aggregation is a common feature of neurodegenerative diseases from Alzheimer's and Parkinson's diseases to amyotrophic lateral sclerosis (ALS). Chaperone proteins such as the metazoan heat shock protein 70 (Hsp70), Hsp40, and Hsp110 complex can identify these misfolded aggregates and restore them to their functional native states. However, previous studies have used a wide range of chaperone complex components and proportions. Using aggregated firefly luciferase as a model substrate, we set out to optimize the stoichiometric ratio for the disaggregation of these aggregates in vitro. We tested ratios of Hsp70:40:110 from 1:10:1 to 1000:100:1 and used the luminescence of firefly luciferin as a measure of disaggregation activity. With this data, we proceeded to refine the canonical Hsp70/40/110 disaggregase network against fused in sarcoma (FUS), a protein that forms pathologic protein aggregates in ALS and frontotemporal dementia (FTD). We used absorbance measurements at 395 nm from a high-throughput plate reader to determine the turbidity levels of FUS aggregates with various combinations of Hsp70/40/110. Together, our findings support the existence of an ideal Hsp70/40/110 system which provides a framework to optimize the disassembly of protein aggregates in other neurodegenerative diseases.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R3204
  4. FASEB J. 2022 May;36 Suppl 1
    Folding state as the Decision Maker in Detecting Misfolded Proteins by Hsp70.
    Chamithi S Karunanayake, Rian DelVecchio, Richard C Page.
      Maintaining cellular proteostasis is challenging due to the constantly changing and crowded cellular environment. Mutations, transcriptional and translational errors, and chemical and pathological stresses in a cell lead to protein misfolding and eventual formation of insoluble toxic aggregates. These aggregates typically result in loss of native protein function and are often associated with conformational diseases such as Alzheimer's, Parkinson's, Huntington's, and various types of cancer. The cellular protein quality control systems are essential for creating a stable cellular environment by resolving the misfolded proteins to uphold a stable proteome. The triage decision for a misfolded protein is regulated by Heat shock protein 70 (Hsp70), the central hub of protein quality control machinery, along with the E3 ubiquitin ligase C-terminus of Hsc70-interacting protein (CHIP). Hsp70 itself helps misfolded "client" proteins to refold and directs protein clients to downstream refolding pathways, whereas Hsp70 interaction with CHIP can lead to CHIP-mediated ubiquitination, ultimately directing the proteins to proteasomal degradation. Understanding the molecular mechanisms that enable the Hsp70/CHIP complex to triage client proteins would allow for the identification of new avenues of treatment for the above-mentioned diseases. With an objective to illustrate how the varying degrees of folding in a model client protein dictate the interaction between Hsp70 and the client, we have designed a spectrum of client proteins we named folding sensor TPRs (FSTPRs). We initially hypothesized that the more unfolded the client higher the affinity towards Hsp70. Circular dichroism (CD) spectroscopy was used to assess the folding states of each FSTPR variant, and biolayer interferometry (BLI) was utilized to quantify the affinities of each FSTPR towards the Hsp70 substrate-binding domain (SBD). During our BLI experiments, we observed a range of threshold unfolding percentages that correspond to the highest affinity. Above and below the threshold range, the affinity decreased. This behavior was recapitulated with a disulfide-locked FSTPR that is folded in the oxidized state and predominantly unfolded in the reduced state. Even though support from further data is necessary, these studies provide us preliminary insight into how Hsp70 interacts with a misfolded client and the role played by folding state in dictating Hsp70/client interactions.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R5829
  5. FASEB J. 2022 May;36 Suppl 1
    A SUMO-dependent Pathway for Cytosolic Protein Quality Control.
    Wei Wang, Michael Matunis.
      Protein quality control (PQC) maintains proteostasis in cells, whereas PQC dysregulation is found in diseases such as cancers, cardiovascular diseases, and neurodegenerative disorders. Over the past few decades, remarkable progress has been made in understanding compartmentalized PQC pathways that operate inside the nucleus and the endoplasmic reticulum (ER). The small ubiquitin-related modifiers (SUMOs), for example, were recently found to participate in a nuclear PQC pathway that involves selective sumoylation of misfolded proteins by the SUMO E3 ligase PML, and subsequent recognition and ubiquitylation by the SUMO-targeted ubiquitin E3 ligase RNF4 (Guo et al., Mol Cell, 2014). Roles of SUMOs in cytoplasmic PQC, however, have not previously been reported. Using yeast mutants and human knockout cell lines, our lab has recently identified a conserved SUMO-dependent pathway for degradation of a cytosolic, misfolded protein model substrate. The substrate consists of GFP fused to an N-terminal nuclear export signal (NES) and a C-terminal hydrophobic degron known as CL1 (NES-GFP-CL1). Using protein stability assays, we observed a decrease in the turnover rate of NES-GFP-CL1 in a yeast SUMO mutant strain and a human U2OS SUMO1 knockout cell line. Further exploration using nuclear and ER-localized substrates revealed that this pathway is specific for soluble, cytosolic proteins. In addition, analysis of a U2OS SUMO2 knockout cell line revealed that the observed PQC pathway is specific for the SUMO1 paralogue. This suggests a distinct mechanism from the previously characterized nuclear PML-SUMO-RNF4 pathway, which targets misfolded proteins modified by SUMO2/3 polymeric chains. Using cellular fractionation studies, we observed an increase in levels of insoluble NES-GFP-CL1 specifically in SUMO1 knockout cells compared to wild type cells. We therefore propose a model where SUMO1 modification of misfolded cytosolic proteins promotes their turnover by enhancing solubility and preventing aggregation. Results from our studies reveal a novel cytosolic PQC regulatory network and provide insights into roles for sumoylation in PQC-associated diseases.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.00R36
  6. Curr Med Chem. 2022 May 08.
    Protein Folding and Molecular Basis of Memory.
    Atta-Ur-Rahman.
      
    DOI:  https://doi.org/10.2174/0929867329666220508173020
  7. Mol Neurobiol. 2022 May 14.
    SUMO1 Modification of Tau in Progressive Supranuclear Palsy.
    Hironori Takamura, Yoshiaki Nakayama, Hidefumi Ito, Taiichi Katayama, Paul E Fraser, Shinsuke Matsuzaki.
      Small ubiquitin-like modifiers (SUMO) have been implicated in several neurodegenerative diseases. SUMO1 conjugation has been shown to promote aggregation and regulate phosphorylation of the tau protein linked to Alzheimer's disease and related tauopathies. The current study has demonstrated that SUMO1 co-localizes with intraneuronal tau inclusions in progressive supranuclear palsy (PSP). Immunoprecipitation of isolated and solubilized tau fibrils from PSP tissues revealed SUMO1 conjugation to a cleaved and N-terminally truncated tau. The effects of SUMOylation were examined using tau-SUMO fusion proteins which showed a higher propensity for tau oligomerization of PSP-truncated tau and accumulation on microtubules as compared to the full-length protein. This was found to be specific for SUMO1 as the corresponding SUMO2 fusion protein did not display a significantly altered cytoplasmic distribution or aggregation of tau. Blocking proteasome-mediated degradation promoted the aggregation of the tau fusion proteins with the greatest effect observed for truncated tau-SUMO1. The SUMO1 modification of the truncated tau in PSP may represent a detrimental event that promotes aggregation and impedes the ability of cells to remove the resulting protein deposits. This combination of tau truncation and SUMO1 modification may be a contributing factor in PSP pathogenesis.
    Keywords:  Neurodegeneration; Neurofibrillary tangles; Protein aggregation; Small ubiquitin-like modifiers (SUMO); Tauopathy; Truncated tau
    DOI:  https://doi.org/10.1007/s12035-022-02734-5
  8. FASEB J. 2022 May;36 Suppl 1
    The Role of Heat Shock Proteins in Amyloid Body Reversal.
    Chloe C Kirk, Michael Bokros, Nathan Balukoff, Phaedra Theodoridis, Taylor Moore, Alex Grunfeld, Arthur Rech Tondin, Maddison Marshall, Stephen Lee.
      The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various physiological and pathological settings, including development, cancer and neurological disorders. We recently reported the surprising discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as "junk" DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts the nucleolus into Amyloid Bodies: a molecular prison of immobilized proteins in an amyloid-like state. This conserved post-translational regulatory pathway enables cells to rapidly and reversibly store an array of endogenous proteins in Amyloid-bodies and enter quiescence in response to severe environmental insults. While many membrane-less compartments have been described as liquid-like (e.g., stress granules, P-bodies, germ cell granules), our discovery of Amyloid-bodies provided evidence of an amyloidogenic process that can physiologically transition biological matter to a solid-like state. The ability of mammalian cells to efficiently dissemble Amyloid-bodies raises a fundamental question: Are mammalian cell disaggregases involved in Amyloid-body disassembly? Here, we show that Amyloid-bodies undergo a multi-step process solid-to-liquid-phase transition to release sequestered proteins and restore nucleolar functions. An RNAi screened identified key heat shock proteins (hsps) that remodel Amyloid-bodies back to the liquid nucleoli on stress termination. The composition of mammalian disaggregases differs considerably from non-metazoans and those involved in disassembly of pathological amyloids in vitro. Activation of mammalian disaggregases and Amyloid-body disassembly is dependent on ATP concentration. Conceptually, this work identifies metazoan disaggregases challenging the widely accepted paradigm that the amyloid state is irreversible in mammalian cells. The data also provides alternative insights into pathogenic amyloids by examining their disassembly in cellular systems.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R3453
  9. Proc Natl Acad Sci U S A. 2022 May 17. 119(20): e2121362119
    Enzymes degraded under high light maintain proteostasis by transcriptional regulation in Arabidopsis.
    Lei Li, Owen Duncan, Diep R Ganguly, Chun Pong Lee, Peter A Crisp, Akila Wijerathna-Yapa, Karzan Salih, Josua Trösch, Barry J Pogson, A Harvey Millar.
      SignificancePhotoinhibitory high light stress in plants leads to increases in markers of protein degradation and transcriptional up-regulation of proteases and proteolytic machinery, but protein homeostasis (proteostasis) of most enzymes is largely maintained under high light, so we know little about the metabolic consequences of it beyond photosystem damage. We developed a technique to look for rapid protein turnover events in response to high light through 13C partial labeling and detailed peptide mass spectrometry. This analysis reveals a light-induced transcriptional program for nuclear-encoded genes, beyond the regulation of photosystem II, to replace key protein degradation targets in plants and ensure proteostasis under high light stress.
    Keywords:  high light; protein turnover; proteostasis; translation
    DOI:  https://doi.org/10.1073/pnas.2121362119
  10. Nature. 2022 May 11.
    Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17.
    Tal Iram, Fabian Kern, Achint Kaur, Saket Myneni, Allison R Morningstar, Heather Shin, Miguel A Garcia, Lakshmi Yerra, Robert Palovics, Andrew C Yang, Oliver Hahn, Nannan Lu, Steven R Shuken, Michael S Haney, Benoit Lehallier, Manasi Iyer, Jian Luo, Henrik Zetterberg, Andreas Keller, J Bradley Zuchero, Tony Wyss-Coray.
      Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1-3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.
    DOI:  https://doi.org/10.1038/s41586-022-04722-0
  11. FASEB J. 2022 May;36 Suppl 1
    The degradation of misfolded proteins in the ER.
    Jeffrey L Brodsky.
      To maintain protein homeostasis (i.e., "proteostasis") and withstand the toxic effects brought about by the presence of misfolded proteins, eukaryotes have evolved a hierarchy of quality control checkpoints along the secretory pathway. The most prominent quality control step in this pathway, which acts during or soon after proteins are synthesized, is endoplasmic reticulum associated degradation (ERAD). The importance of this pathway is underscored by the fact that ~80 different protein substrates of the ERAD pathway have been linked to human disease. Although most misfolded proteins in the secretory pathway are eliminated by ERAD, others can exit the ER in COPII vesicles and are instead turned over by lysosomal proteases. This post-ER quality control event requires the ESCRT machinery. A different class of secreted proteins, particularly those that are aggregation-prone, can alternatively be degraded by ER-phagy. To date, it remains elusive how these diverse misfolded proteins--which can trigger various stress responses--are selected for different fates. However, by constructing a collection of model substrates and examining wild-type and disease-associated mutant forms of various proteins, we are beginning to define the requirements for the targeted selection of misfolded proteins in the secretory pathway for one fate versus another. This pursuit represents a vital step toward the development of pharmaceuticals that might one day repair folding-defective proteins. Indeed, a growing number of clinical and pre-clinical drugs that repair ERAD and other quality control substrates have shown efficacy in various disease models. In this presentation, each of these topics will be discussed and future research directions defined.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I136
  12. FASEB J. 2022 May;36 Suppl 1
    Effects of Aging on Proteome Dynamics in Mice Brain Microvessels: ROS Scavengers, mRNA/Protein Stability, Glycolytic Enzymes, Mitochondrial Complexes, and Basement Membrane Components.
    Partha K Chandra, Sinisa Cikic, Ibolya Rutkai, Jessie J Guidry, Prasad V G Katakam, Ricardo Mostany, David W Busija.
       BACKGROUND: Aging is an unavoidable stress with ever-increasing detrimental effects on the brain microvasculature, which affects neuronal health/function and adds vulnerability to strokes and neurological diseases. In this study, we performed an extensive examination of proteins involved in the structure and function of mouse brain cortical microvessels (MVs) using a discovery-based quantitative proteomic approach.
    METHODS: Cortical MVs were isolated from age-matched, male and female, young (4-6 months), middle-aged (12-14 months), and old (20-21 months) mice obtained from Jackson Laboratory [Tg(Thy1-EGFP)MJrs/J] (Jax No. 007788) and bred in a C57B16J background. The presence of end-arterioles, capillaries, and venules in MVs was confirmed by light microscopy and by alkaline phosphate staining. Proteomics analysis was performed using liquid chromatography/mass spectrometry.
    RESULTS: Most differentially expressed (DE) proteins (> 90%) showed no significant disparities between the sexes; however, some significant DE proteins showing sexual differences in MVs decreased from percentage in young (8.3%), to middle-aged (3.7%), to old (0.5%) mice. Therefore, we combined male and female data for age-dependent comparisons but noted sex differences for examination. Key proteins involved in the oxidative stress response, mRNA or protein stability, basement membrane (BM) composition, aerobic glycolysis, and mitochondrial function were significantly altered with aging. Relative abundance of superoxide dismutase-1/-2, catalase, and thioredoxin were reduced with aging. Proteins participating in either mRNA degradation or pre-mRNA splicing were significantly increased in old mice MVs, whereas protein stabilizing proteins decreased. Glycolytic proteins were not affected in middle age, but the relative abundance decreased in MVs of old mice. Although most of the 41 examined proteins composing mitochondrial Complexes I-V were reduced in old mice, six of these proteins showed a significant reduction in middle-aged mice, but the relative abundance increased in fourteen proteins. Nidogen, collagen, and laminin family members as well as perlecan showed differing patterns during aging, indicating BM reorganization starting in middle age.
    CONCLUSIONS: We suggest that increased oxidative stress during aging leads to adverse protein profile changes of brain cortical MVs that affect mRNA/protein stability, BM integrity, and ATP synthesis capacity.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R1918
  13. FASEB J. 2022 May;36 Suppl 1
    Brain endothelial cell barrier function is compromised by autophagy depletion.
    Seul-Ki Park, Jae Min Cho, Sohom Mookherjee, Revi Brown, Jaimee Jacob, Weiquan Zhu, Zhonglou Sun, J David Symons.
      Age-associated cerebral hypoperfusion and heightened blood brain barrier (BBB) permeability contribute importantly to vascular cognitive impairment. Earlier we reported that mRNA and protein expression of autophagy markers is repressed (p<0.05) in endothelial cells (ECs) from older (24-month) mice and older (> 68 y) male subjects that exhibit concurrent peripheral arterial dysfunction. Of note, adult mice with inducible EC specific depletion of autophagy related gene 3 (Atg3) display endothelium-dependent dysfunction (p<0.05) of femoral and middle cerebral arteries, whereas smooth muscle function is intact in both vascular beds. While these findings indicate repressed EC autophagy associates strongly with arterial dysfunction, the impact of EC autophagy on BBB permeability is unknown. Because EC autophagy repression mimics an aging phenotype, we hypothesized that BBB permeability is heightened in mice with EC specific Atg3 depletion (Atg3EC-/- ) vs. wild type littermates (WT). In support of this, Evans blue dye was more abundant (p<0.05) in brains from Atg3EC-/- vs. WT littermates (n=6 per group). Further, fluorescence assisted cell sorting results indicated a greater number (p<0.05) of white blood cells, microglia, and neutrophils in brains from Atg3EC-/- vs. WT mice (n=4 per group). Using a reductionist approach we tested whether human brain microvascular ECs (HBMVECs) with autophagy depletion exhibit heightened permeability. Results from electric cell-substrate impedance sensing procedures indicate that permeability was greater (p<0.05) in HBMVECs after : (i) IL-1β (positive control) vs. vehicle-treatment; (ii) 3-methyladenine (autophagy initiation inhibitor) vs. vehicle-treatment; and (iii) CRISPR-cas9 mediated Atg3 knock-down (Atg3 KD) vs. transfection with negative sgRNA (control) (p<0.05, 24 wells per treatment x three repetitions). In addition, Atg3 KD HBMVECs displayed reduced protein expression of: (i) Atg3; (ii) zonula occludens-1; (iii) platelet endothelial cell adhesion molecule-1; (iv) vascular endothelial cadherin; and (v) glucose transporter 1 (p<0.05, n=6). These data provide evidence that Atg3 depletion jeopardizes BBB integrity.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R5826
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