945 research outputs found

    Autophagy and Redox Homeostasis in Parkinson’s:A Crucial Balancing Act

    Get PDF
    Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson’s is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson’s. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson’s

    The ATG5 interactome links clathrin-mediated vesicular trafficking with the autophagosome assembly machinery

    Get PDF
    Autophagosome formation involves the sequential actions of conserved ATG proteins to coordinate the lipidation of the ubiquitin-like modifier Atg8-family proteins at the nascent phagophore membrane. Although the molecular steps driving this process are well understood, the source of membranes for the expanding phagophore and their mode of delivery are only now beginning to be revealed. Here, we have used quantitative SILAC-based proteomics to identify proteins that associate with the ATG12–ATG5 conjugate, a crucial player during Atg8-family protein lipidation. Our datasets reveal a strong enrichment of regulators of clathrin-mediated vesicular trafficking, including clathrin heavy and light chains, and several clathrin adaptors. Also identified were PIK3C2A (a phosphoinositide 3-kinase involved in clathrin-mediated endocytosis) and HIP1R (a component of clathrin vesicles), and the absence of either of these proteins alters autophagic flux in cell-based starvation assays. To determine whether the ATG12–ATG5 conjugate reciprocally influences trafficking within the endocytic compartment, we captured the cell surface proteomes of autophagy-competent and autophagy-incompetent mouse embryonic fibroblasts under fed and starved conditions. We report changes in the relative proportions of individual cell surface proteins and show that cell surface levels of the SLC7A5-SLC3A2 amino acid transporter are influenced by autophagy capability. Our data provide evidence for direct regulatory coupling between the ATG12–ATG5 conjugate and the clathrin membrane trafficking system and suggest candidate membrane proteins whose trafficking within the cell may be modulated by the autophagy machinery. Abbreviations: ATG, autophagy related; BafA1, bafilomycin A(1); GFP, green fluorescent protein; HIP1R, huntingtin interacting protein 1 related; MEF, mouse embryo fibroblast; PIK3C2A, phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha; SILAC, stable isotope labelling with amino acids in culture; SQSTM1, sequestosome 1; STRING, search tool for the retrieval of interacting genes/protein

    Self-eating on demand:autophagy in cancer and cancer therapy

    Get PDF
    Macroautophagy, the major lysosomal pathway for recycling intracellular components including whole organelles, has emerged as a key process modulating tumorigenesis, tumor–stroma interactions, and cancer therapy. An impressive number of studies over the past decade have unraveled the plastic role of autophagy during tumor development and dissemination. The discoveries that autophagy may either support or repress neoplastic growth and contextually favor or weaken resistance and impact antitumor immunity have spurred efforts from many laboratories trying to conceptualize the complex role of autophagy in cancer using cellular and preclinical models. This complexity is further accentuated by recent findings highlighting that various autophagy-related genes have roles beyond this catabolic mechanism and interface with oncogenic pathways, other trafficking and degradation mechanisms and the cell death machinery. From a therapeutic perspective, knowledge of how autophagy modulates the tumor microenvironment is crucial to devise autophagy-targeting strategies using smart combination of drugs or anticancer modalities. This eBook contains a collection of reviews by autophagy researchers and provides a background to the state-of-the-art in the field of autophagy in cancer, focusing on various aspects of autophagy regulation ranging from its molecular components to its cell autonomous role, e.g. in cell division and oncogenesis, miRNAs regulation, cross-talk with cell death pathways as well as cell non-autonomous role, e.g. in secretion, interface with tumor stroma and clinical prospects of autophagy-based biomarkers and autophagy modulators in anticancer therapy. This eBook is part of the TransAutophagy initiative to better understand the clinical implications of autophagy in cancer

    Autophagy coordinates chondrocyte development and early joint formation in zebrafish

    Get PDF
    Autophagy is a catabolic process responsible for the removal of waste and damaged cellular components by lysosomal degradation. It plays a key role in fundamental cell processes, including ER stress mitigation, control of cell metabolism, and cell differentiation and proliferation, all of which are essential for cartilage cell (chondrocyte) development and survival, and for the formation of cartilage. Correspondingly, autophagy dysregulation has been implicated in several skeletal disorders such as osteoarthritis and osteoporosis. To test the requirement for autophagy during skeletal development in zebrafish, we generated an atg13 CRISPR knockout zebrafish line. This line showed a complete loss of atg13 expression, and restricted autophagic activity in vivo. In the absence of autophagy, chondrocyte maturation was accelerated, with chondrocytes exhibiting signs of premature hypertrophy. Focussing on the jaw element, autophagy disruption affected joint articulation causing restricted mouth opening. This gross behavioural phenotype corresponded with a failure to thrive, and death in homozygote atg13 nulls within 17 days. Taken together, our results are consistent with autophagy contributing to the timely regulation of chondrocyte maturation and for extracellular matrix formation

    Release and Establishment of Megamelus scutellaris (Hemiptera: Delphacidae) on Waterhyacinth in Florida

    Get PDF
    More than 73,000 Megamelus scutellaris (Hemiptera: Delphacidae) were released in Florida over a 2 to 3 yr period at 10 sites in an attempt to establish sustainable populations on waterhyacinth, Eichhornia crassipes Mart. Solms (Commelinales: Pontederiaceae). Insect populations persisted at most sites including those furthest north and consecutive overwintering was confirmed in as many as three times at some sites. Establishment appeared to be promoted at sites with some cover or shading compared to open areas. Insects readily dispersed over short distances which made detection and monitoring difficultFil: Tipping, Philip W.. Invasive Plant Research Laboratory; Estados UnidosFil: Sosa, Alejandro Joaquín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para el Estudio de Especies Invasivas; ArgentinaFil: Pokorny, Eileen N.. Invasive Plant Research Laboratory; Estados UnidosFil: Foley, Jeremiah. Invasive Plant Research Laboratory; Estados UnidosFil: Schmitz, Don C.. Florida Fish and Wildlife Conservation Commission; Estados UnidosFil: Lane, Jon S.. U.S. Army Corps of Engineers; Estados UnidosFil: Rodgers, Leroy. South Florida Water Management District; Estados UnidosFil: Mccloud, Lori. St. Johns River Water Management District; Estados UnidosFil: Livingston-Way, Pam. St. Johns River Water Management District; Estados UnidosFil: Cole, Matthew S.. St. Johns River Water Management District; Estados UnidosFil: Nichols, Gary. St. Johns River Water Management District; Estados Unido

    Hoping to Teach Someday? Inquire Within: Examining Inquiry-Based Learning with First-Semester Undergrads

    Get PDF
    Using case study method, this study examines the impact of an inquiry-based learning program among a cohort of first-semester undergraduates (n=104) at a large public university in the southeastern United States who are aspiring to become teachers. The Boyer Commission (1999) asserted that inquiry-based learning should be the foundation of higher education curricula. Even though inquiry pedagogies are emphasized in teacher education, many prospective teacher candidates have limited experience with inquiry as a constructivist practice from their K-12 settings. This study investigates the effects and first-semester undergraduates’ perceptions of an inquiry-based learning project. The research is grounded in Knowledge Building Theory (Scardamalia & Bereiter, 2006), which posits that knowledge building is comprised of three components: 1) inquiry driven questions, 2) epistemic artifacts, and 3) collective spaces for collaboration. The study found that inquiry projects had positive effects on participants’ understanding of: the complexity of educational issues; the overall inquiry process; and a future career in teaching. Using Knowledge Building Theory, the findings are discussed and analyzed to posit a conceptual model of the entire inquiry process, called the Inquiry Processing Cycle

    Briefing: United Kingdom Universal Periodic Review: Responses to Fourth Cycle Recommendations

    Get PDF
    The Universal Periodic Review (UPR) is a process under the auspice of the Human Rights Council (HRC) which all United Nations (UN) member states participate in every four-and-a-half years. The outcome is a set of recommendations for the state under review to improve the promotion and protection of human rights. These should be implemented by the state between cycles. In March 2022, the fourth UPR cycle began, and the United Kingdom was reviewed in November 2022. It received 331 recommendations from states
    • …
    corecore