Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease.
ABSTRACT Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is increasingly implicated in various neurodegenerative diseases. Deregulated Cdk5 activity has been associated with neuronal death, but the underlying mechanisms are not well understood. Here we report an unexpected role for Cdk5 in the regulation of induced autophagy in neurons. We have identified endophilin B1 (EndoB1) as a Cdk5 substrate, and show that Cdk5-mediated phosphorylation of EndoB1 is required for autophagy induction in starved neurons. Furthermore, phosphorylation of EndoB1 facilitates EndoB1 dimerization and recruitment of UVRAG (UV radiation resistance-associated gene). More importantly, Cdk5-mediated phosphorylation of EndoB1 is essential for autophagy induction and neuronal loss in models of Parkinson’s disease. Our findings not only establish Cdk5 as a critical regulator of autophagy induction, but also reveal a role for Cdk5 and EndoB1 in the pathophysiology of Parkinson’s disease through modulating autophagy.
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ABSTRACT: Autophagy is a ubiquitous catabolic process involving degradation of damaged organelles and protein aggregates. It shows cytoprotective effects in many cell types and helps to maintain cell homeostasis. In many glomerular diseases, podocyte damage leads to the disruption of the renal filtration barrier and subsequent proteinuria. Puromycin aminonucleoside (PAN) which induces podocyte apoptosis in vitro and in vivo is widely used for studying the pathophysiology of glomerular diseases. It has been shown that PAN induces autophagy in podocytes. However, the relationship between autophagy and apoptosis in PAN treated human podocytes is not known and the role of PAN-induced autophagy in podocyte survival remains unclear. Here we demonstrate that PAN induced autophagy in human podocytes prior to apoptosis which was featured with the activation of mTOR complex 1 (mTORC1). When the PAN-induced autophagy was inhibited by 3-methyladenine (3-MA) or chloroquine (CQ), podocyte apoptosis increased significantly along with the elevation of active caspase-3. Under such circumstance, the podocyte cytoskeleton was also disrupted. Collectively, our results suggested that the induced autophagy may be an early adaptive cytoprotective mechanism for podocyte survival after PAN treatment.Biochemical and Biophysical Research Communications 12/2013; 443(2). DOI:10.1016/j.bbrc.2013.12.015 · 2.28 Impact Factor
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ABSTRACT: Macroautophagy maintains cellular homeostasis through targeting cytoplasmic contents and organelles into autophagosomes for degradation. This process begins with the assembly of protein complexes on isolation membrane to initiate the formation of autophagosome, followed by its nucleation, elongation and maturation. Fusion of autophagosomes with lysosomes then leads to degradation of the cargo. In the past decade, significant advances have been made on the identification of molecular players that are implicated in various stages of macroautophagy. Post-translational modifications of macroautophagy regulators have also been demonstrated to be critical for the selective targeting of cytoplasmic contents into autophagosomes. In addition, recent demonstration of distinct macroautophagy regulators has led to the identification of different subtypes of macroautophagy. Since deregulation of macroautophagy is implicated in diseases including neurodegenerative disorders, cancers and inflammatory disorders, understanding the molecular machinery of macroautophagy is crucial for elucidating the mechanisms by which macroautophagy is deregulated in these diseases, thereby revealing new potential therapeutic targets and strategies. Here we summarize current knowledge on the regulation of mammalian macroautophagy machineries and their disease-associated deregulation.Biochimica et Biophysica Acta 07/2011; 1812(11):1490-7. DOI:10.1016/j.bbadis.2011.07.005 · 4.66 Impact Factor
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ABSTRACT: Autophagy is an evolutionarily conserved homeostatic process for the turnover of cellular contents, organelles and misfolded proteins through the lysosomal machinery. Recently, the involvement of autophagy in the pathophysiology of neurodegenerative diseases has attracted considerable interest because autophagy deregulation has been linked to some of these neurodegenerative disorders. This interest is further heightened by the demonstration that various autophagic pathways, including macroautophagy and chaperone-mediated autophagy, are implicated in the turnover of proteins that are prone to aggregation in cellular or animal disease models. These observations have stimulated new awareness in the pivotal role of the autophagic pathways in neurodegenerative disease pathophysiology, and have sparked extensive research aimed at deciphering the mechanisms by which autophagy is altered in these disorders. Here, we summarize the latest advances in our understanding of the role of autophagy deregulation in Parkinson's, Alzheimer's and Huntington's disease.Journal of Neurochemistry 05/2011; 118(3):317-25. DOI:10.1111/j.1471-4159.2011.07314.x · 4.24 Impact Factor