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BioRxiv : the Preprint Server For... Jun 2024Injury can cause differentiated cells to undergo massive reprogramming to become proliferative to repair tissue via a cellular program called paligenosis. Gastric...
Injury can cause differentiated cells to undergo massive reprogramming to become proliferative to repair tissue via a cellular program called paligenosis. Gastric digestive-enzyme-secreting chief cells use paligenosis to reprogram into progenitor-like Spasmolytic-Polypeptide Expressing Metaplasia (SPEM) cells. Stage 1 of paligenosis is to downscale mature cell architecture via a process involving lysosomes. Here, we noticed that sulfated glycoproteins (which are metaplasia and cancer markers in mice and humans) were not digested during paligenosis but excreted into the gland lumen. Various genetic and pharmacological approaches showed that endoplasmic reticulum membranes and secretory granule cargo were also excreted and that the process proceeded in parallel with, but was independent lysosomal activity. 3-dimensional light and electron-microscopy demonstrated that excretion occurred via unique, complex, multi-chambered invaginations of the apical plasma membrane. As this lysosome-independent cell cleansing process does not seem to have been priorly described, we termed it "cathartocytosis". Cathartocytosis allows a cell to rapidly eject excess material (likely in times of extreme stress such as are induced by paligenosis) without waiting for autophagic and lysosomal digestion. We speculate the ejection of sulfated glycoproteins (likely mucins) would aid in downscaling and might also help bind and flush pathogens (like which causes SPEM) away from tissue.
PubMed: 38915707
DOI: 10.1101/2024.06.11.598489 -
BioRxiv : the Preprint Server For... Jun 2024Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological...
UNLABELLED
Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed Aβ localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) Aβ pathology and cognitive deficits in AD mice. The addition of recombinant LAL and neuronal LAL overexpression prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal Aβ. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with Aβ , and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of Aβ in neuronal lysosomes to drive AD amyloid pathology.
SUMMARY
Cellular and molecular drivers of late-onset Alzheimer's disease (LOAD) are unknown, though several risk factors account for the majority of disease incidence . Though diverse in their biological natures, each of these risk exposures converge on a shared pathological progression with the accumulation of amyloid early in the disease. Human genetic and transcriptomic studies suggest a role for altered lipid metabolism , though the mechanism has been unknown. Here, using two common midlife risk exposures for LOAD, we found that dysfunctional lipophagy caused by the loss of lysosomal acid lipase (LAL) promotes early LOAD pathogenesis. Both midlife obesity and heavy alcohol reduced neuronal LAL, causing an increase in neuronal lysosomal lipid, and a subsequent accumulation of Aβ in the extra-lysosomal cytosol. This loss of LAL preceded and promoted Aβ pathology and cognitive deficits in AD mice. The addition of recombinant LAL and neuronal LAL overexpression prevented increases in amyloid and improved cognition. In human brain, LAL declined with age in healthy subjects, similar to rodents, showing robust losses in LOAD subjects with polymerase pausing. Together, this implicates neuronal LAL loss in LOAD pathogenesis and presents LAL as a promising diagnostic, preventative, and/or therapeutic target for AD.
PubMed: 38915509
DOI: 10.1101/2024.06.09.596693 -
The Journal of Cell Biology Aug 2024The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance...
The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance was observed in tissues from mouse models and fibroblasts from patients with neurodegenerative diseases, accompanied by enhanced mTOR signaling and impaired autophagic flux, while the underlying mechanism remains elusive. Here, we find that endogenous STAU1 forms dynamic cytoplasmic condensate in normal and tumor cell lines, as well as in mouse Huntington's disease knockin striatal cells. STAU1 condensate recruits target mRNA MTOR at its 5'UTR and promotes its translation both in vitro and in vivo, and thus enhanced formation of STAU1 condensate leads to mTOR hyperactivation and autophagy-lysosome dysfunction. Interference of STAU1 condensate normalizes mTOR levels, ameliorates autophagy-lysosome function, and reduces aggregation of pathological proteins in cellular models of neurodegenerative diseases. These findings highlight the importance of balanced phase separation in physiological processes, suggesting that modulating STAU1 condensate may be a strategy to mitigate the progression of neurodegenerative diseases with STAU1 overabundance.
Topics: RNA-Binding Proteins; TOR Serine-Threonine Kinases; Animals; Humans; Autophagy; Mice; Protein Biosynthesis; Cytoskeletal Proteins; Neurodegenerative Diseases; Lysosomes; Signal Transduction; Huntington Disease
PubMed: 38913026
DOI: 10.1083/jcb.202311127 -
International Journal of Biological... Jun 2024Autophagy is a process that eliminates damaged cells and malfunctioning organelles via lysosomes, which is closely linked to cancer. Primaquine (PQ) was reported to...
Autophagy is a process that eliminates damaged cells and malfunctioning organelles via lysosomes, which is closely linked to cancer. Primaquine (PQ) was reported to impede autophagy flow by preventing autophagosomes from fusing with lysosomes at the late stage of autophagy. It will lead to cellular metabolic collapse and programmed cell death. Excessive or extended autophagy enhances the efficacy of chemotherapeutic drugs in cancer prevention. The utilization of autophagy inhibition in conjunction with chemotherapy has become a prevalent and reliable approach for the safe and efficient treatment of cancer. In this work, an acid-sensitive nanoprodrug (O@PD) targeting CD44 receptors was produced using Schiff-base linkages or electrostatic interactions from oxidized hyaluronic acid (OHA), PQ, and doxorubicin (DOX). The CD44-targeting prodrug system in triple-negative breast cancer (TNBC) cells was designed to selectively release DOX and PQ into the acidic tumor microenvironment and cellular endosomes. DOX was employed to investigate the cellular uptake and ex-vivo drug distribution of O@PD nanoprodrugs. PQ-induced autophagy suppression combined with DOX has a synergistic fatal impact in TNBC. O@PD nanoprodrugs demonstrated robust anticancer efficacy as well as excellent biological safety, making them suitable for clinical use.
PubMed: 38909736
DOI: 10.1016/j.ijbiomac.2024.133360 -
Nature Chemical Biology Jun 2024Sterol-binding proteins are important regulators of lipid homeostasis and membrane integrity; however, the discovery of selective modulators can be challenging due to...
Sterol-binding proteins are important regulators of lipid homeostasis and membrane integrity; however, the discovery of selective modulators can be challenging due to structural similarities in the sterol-binding domains. We report the discovery of potent and selective inhibitors of oxysterol-binding protein (OSBP), which we term oxybipins. Sterol-containing chemical chimeras aimed at identifying new sterol-binding proteins by targeted degradation, led to a significant reduction in levels of Golgi-associated proteins. The degradation occurred in lysosomes, concomitant with changes in protein glycosylation, indicating that the degradation of Golgi proteins was a downstream effect. By establishing a sterol transport protein biophysical assay panel, we discovered that the oxybipins potently inhibited OSBP, resulting in blockage of retrograde trafficking and attenuating Shiga toxin toxicity. As the oxybipins do not target other sterol transporters and only stabilized OSBP in intact cells, we advocate their use as tools to study OSBP function and therapeutic relevance.
PubMed: 38907112
DOI: 10.1038/s41589-024-01653-x -
Current Opinion in Cell Biology Jun 2024Lysosomes are central to the maintenance of protein and organelle homeostasis in cells. Optimal lysosome function is particularly critical for neurons which are... (Review)
Review
Lysosomes are central to the maintenance of protein and organelle homeostasis in cells. Optimal lysosome function is particularly critical for neurons which are long-lived, non-dividing and highly polarized with specialized compartments such as axons and dendrites with distinct architecture, cargo, and turnover requirements. In recent years, there has been a growing appreciation for the role played by axonal lysosome transport in regulating neuronal development, its maintenance and functioning. Perturbations to optimal axonal lysosome abundance leading to either strong accumulations or dearth of lysosomes are both linked to altered neuronal health and functioning. In this review we highlight how two critical regulators of axonal lysosome transport and abundance, the small GTPase Arl8 and the adaptor protein JIP3, aid in maintaining axonal lysosome homeostasis and how alterations to their levels and activity could contribute to neurodevelopmental and neurodegenerative diseases.
PubMed: 38905918
DOI: 10.1016/j.ceb.2024.102382 -
Bioconjugate Chemistry Jun 2024Currently, clinical therapeutic strategies for nasopharyngeal carcinoma (NPC) confront insurmountable dilemmas in which surgical resection is incomplete and...
Currently, clinical therapeutic strategies for nasopharyngeal carcinoma (NPC) confront insurmountable dilemmas in which surgical resection is incomplete and chemotherapy/radiotherapy has significant side effects. Phototherapy offers a maneuverable, effective, and noninvasive pattern for NPC therapy. Herein, we developed a lysosome-targeted and pH-responsive nanophototheranostic for near-infrared II (NIR-II) fluorescence imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) of NPC. A lysosome-targeted S-D-A-D-S-type NIR-II phototheranostic molecule (IRFEM) is encapsulated within the acid-sensitive amphiphilic DSPE-Hyd-PEG2k to form IRFEM@DHP nanoparticles (NPs). The prepared IRFEM@DHP exhibits a good accumulation in the acidic lysosomes for facilitating the release of IRFEM, which could disrupt lysosomal function by generating an amount of heat and ROS under laser irradiation. Moreover, the guidelines of NIR-II fluorescence enhance the accuracy of PTT/PDT for NPC and avoid damage to normal tissues. Remarkably, IRFEM@DHP enable efficient antitumor effects both and , opening up a new avenue for precise NPC theranostics.
PubMed: 38904455
DOI: 10.1021/acs.bioconjchem.4c00225 -
Chemical Society Reviews Jun 2024The Golgi apparatus is an essential organelle constructed by the stacking of flattened vesicles, that is widely distributed in eukaryotic cells and is dynamically... (Review)
Review
The Golgi apparatus is an essential organelle constructed by the stacking of flattened vesicles, that is widely distributed in eukaryotic cells and is dynamically regulated during cell cycles. It is a central station which is responsible for collecting, processing, sorting, transporting, and secreting some important proteins/enzymes from the endoplasmic reticulum to intra- and extra-cellular destinations. Golgi-specific fluorescent probes provide powerful non-invasive tools for the real-time and visualization of the temporal and spatial fluctuations of bioactive species. Over recent years, more and more Golgi-targeting probes have been developed, which are essential for the evaluation of diseases including cancer. However, when compared with systems that target other important organelles ( lysosomes and mitochondria), Golgi-targeting strategies are still in their infancy, therefore it is important to develop more Golgi-targeting probes. This review systematically summarizes the currently reported Golgi-specific fluorescent probes, and highlights the design strategies, mechanisms, and biological uses of these probes, we have structured the review based on the different targeting groups. In addition, we highlight the future challenges and opportunities in the development of Golgi-specific imaging agents and therapeutic systems.
PubMed: 38904177
DOI: 10.1039/d3cs00171g -
Frontiers in Aging Neuroscience 2024Parkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes...
BACKGROUND
Parkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear.
METHODS
This study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson's disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson's Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD.
RESULTS
Elevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005).
CONCLUSION
This genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.
PubMed: 38903897
DOI: 10.3389/fnagi.2024.1380483 -
BioRxiv : the Preprint Server For... Apr 2024Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, ) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to...
Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, ) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified a zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis. , LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling. , endothelial-specific expression of constitutively active leads to excessive angiogenesis, similar to the mutants. Increased angiogenesis is also evident in zebrafish harboring mutations in , the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.
PubMed: 38903077
DOI: 10.1101/2024.04.01.587559