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    • Other interventions inhibit autophagy including

    2018-11-09

    Other interventions inhibit autophagy, including inhibitors of the protein kinases, ULK1 and ULK2 (Egan et al., 2015, Petherick et al., 2015), and the class III phosphoinositide-3-kinase, (VPS34) (Bago et al., 2014; Dowdle et al., 2014; Ronan et al., 2014). VPS34 is a component of the BCL-2 interacting moesin-like coiled-coil protein 1, (Beclin-1) signaling complex. Beclin-1 contains a BH3 domain, allowing it to interact with other BH3 containing proteins, including B cell CLL/lymphoma 2 (BCL-2), and the downstream functions of the Beclin-1 complex can differ with respect to autophagy, dependent on the Zalcitabine found in complex with it (Sinha and Levine, 2008). Other components of the complex include ultraviolet irradiation resistant-associated gene (UVRAG), SH3GLB2, (also known as BIF-1), and activating molecule in Beclin-1 regulated autophagy 1 (AMBRA1). Some of these interactions can be pharmacologically targeted. BH3 mimetics like Venetoclax, which was designed to induce apoptosis by blocking BCL-2 interactions at the mitochondria, also disrupt interactions between Beclin-1 and BCL-2 to induce autophagy (Maiuri et al., 2007). However, this mechanism has been challenged and it has been proposed that BH3 mimetics may only affect autophagy via indirect mechanisms that occur sometime after they have hit their direct target (Reljic et al., 2016). A cell-permeable peptide, Tat-Beclin1, disrupts another interaction in the Beclin-1 complex to induce autophagy (Shoji-Kawata et al., 2013). In addition to the many drugs that can modulate autophagy (Levine et al., 2015), non-pharmacological interventions including caloric restriction and exercise also induce autophagy. For example, exercise targets the Beclin-1 signaling complex to induce autophagy that can protect mice against diabetes (He et al., 2012). Two ubiquitin-like conjugation systems elongate the autophagosome membrane. The ubiquitin-like protein ATG12 is conjugated to ATG5 in a process requiring the E1-like enzyme, ATG7. A similar lipid conjugation system (also using ATG7) attaches phosphatidylethanolamine (PE) to the Microtubule Associated Protein 1 light chain 3 (MAP1LC3) and GABA type A receptor-associated protein (GABARAP) families of proteins. Pharmacological inhibitors of ATG7 that block these processes have been discussed at meetings. LC3-PE conjugation occurs after cleavage and processing of LC3 by the protease, ATG4B, which can also be inhibited pharmacologically (Akin et al., 2014). LC3-PE is incorporated into the autophagosome membrane and is the most common marker of autophagy (Klionsky et al., 2016). The final step is to fuse the autophagosome with the lysosome by the SNARE protein, STX17 (Itakura et al., 2012). This step can be blocked with lysosomal inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) or Bafilomycin A1. Once fusion is complete, the lysosomal hydrolases degrade the contents of the autophagosomes producing amino acids, nutrients, and lipids that are available to fuel protein and other macromolecular synthesis and metabolism.
    Targeting Autophagy in Neurological Diseases Autophagy has been implicated in neurodegenerative disease for two reasons. First, defects in autophagy cause neurodegeneration. For example, although systemic knockout of Atg7 leads to neonatal death in mice (Komatsu et al., 2005), neuronal deletion allows the mice to survive to adulthood, however the animals succumb to neurodegenerative disease (Komatsu et al., 2006). Moreover, when Atg7 is acutely deleted in all cells in adult animals, the most common cause of death is neurodegenerative disease with accumulation of ubiquitinated protein aggregates (Karsli-Uzunbas et al., 2014). A mutation in the human ATG5 gene that inhibits autophagy also causes congenital ataxia and developmental delay (Kim et al., 2016). The second link to neurodegenerative diseases including Alzheimers Disease (AD), Parkinson\'s Disease (PD), and Huntington\'s Disease (HD) is the involvement of toxic protein aggregates that can be degraded via autophagy in the pathology of all of these diseases (Nah et al., 2015).