Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease

ArticleinNature Cell Biology 13(6):734 · June 2011with5 Reads
DOI: 10.1038/ncb0611-734d · Source: PubMed
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.
    • "In other cases, compounds are inversely concerned with cytotoxic mechanisms of autophagy in PD. 6-OHDA, one of the most commonly used neurotoxins for modeling degeneration of dopaminergic neurons in PD, is able to induce autophagic cell death, which can be reverted by pretreated with autophagy inhibition by 3-methyladenine (3-MA) or AKT activation [37, 38]. MPTP also triggers neuronal loss with Cdk-5-associated autophagy activation [36]. The two compounds above are often used for building PD models but not for treatment. "
    [Show abstract] [Hide abstract] ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the preferential death of dopaminergic neurons. In the past two decades, great progress has been made toward understanding the pathogenesis of PD; however, its precise pathogenesis still remains unclear. Recently, accumulating evidence has suggested that macroautophagy (herein referred to as autophagy) is tightly linked to PD. Dysregulation of autophagic pathways has been observed in the brains of PD patients and in animal models of PD. More importantly, a number of PD-associated proteins, such as α-synuclein, LRRK2, Parkin and PINK1 have been further revealed to be involved in autophagy. Thus, it is now acknowledged that constitutive autophagy is essential for neuronal survival and that dysregulation of autophagy leads to PD. In this review, we focus on summarizing the relationships amongst PD-associated proteins, autophagy and PD. Moreover, we also demonstrate some autophagymodulating compounds and autophagic microRNAs in PD models, which may provide better promising strategies for potential PD therapy.
    Full-text · Article · Jul 2015
    • "Initially identified through structural homology with CDK2 [75,76], and independently isolated as a proline-directed histone H1 kinase from bovine brain, CDK5/p35 was found to phosphorylate histone H1 and retinoblastoma protein (pRb)777879. However, this kinase is not involved in coordination of cell cycle progression, and instead exerts its functions mainly in the central nervous system, where it promotes neurite extension, neuronal migration, synapse formation during brain development, synaptic plasticity and synaptic activities in mature neurons, axonal guidance, neuronal development and differentiation, and further participates in regulation of autophagy4344458081828384. Moreover several extraneuronal functions of CDK5 have been reported including apoptosis in nonneuronal model systems and insulin secretion in pancreatic cells [46,85,86]. "
    [Show abstract] [Hide abstract] ABSTRACT: Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported.
    Full-text · Article · Mar 2015
    • "Nutrient-deprived 3D5 cells bearing high level of α-syn (i.e., 9 days of induction or more) are comparable to nondeprived counterparts in the level of LC3-II and autophagic flux, suggesting these cells have reached their maximum capacity in autophagy so that nutrient deprivation could not enhance autophagy to accelerate α-syn degradation as effectively as it could in cells without α-syn induction. It is worth noting that α-syn overexpression has been shown to activate or impair autophagy in different studies (Winslow et al., 2010; Choubey et al., 2011; Wong et al., 2011). Based on the results obtained from our cell models, we supported the role of α-syn in autophagy activation. "
    [Show abstract] [Hide abstract] ABSTRACT: Abnormal accumulation of filamentous α-synuclein (α-syn) in neurons, regarded as Lewy bodies(LBs), are a hallmark of Parkinson disease (PD). Although the exact mechanism(s) underlying LBs formation remains unknown, autophagy and ER stress response have emerged as two important pathways affecting α-syn aggregation. In present study we tested whether cells with the tetracycline-off inducible overexpression of α-syn and accumulating α-syn aggregates can benefit from autophagy activation elicited by nutrient deprivation, since this approach was reported to effectively clear cellular polyglutamine aggregates. We found that nutrient deprivation of non-induced cells did not affect cell viability, but significantly activated autophagy reflected by increasing the level of autophagy marker LC3-II and autophagic flux and decrease of endogenous α-syn. Cells with induced α-syn expression alone displayed autophagy activation in an α-syn dose-dependent manner to reach a level comparable to that found in non-induced, nutrient deprived counterparts. Nutrient deprivation also activated autophagy further in α-syn induced cells, but the extent was decreased with increase of α-syn dose, indicating α-syn overexpression reduces the responsiveness of cells to nutrient deprivation. Moreover, the nutrient deprivation enhanced α-syn aggregations concomitant with significant increase of apoptosis as well as ER stress response, SREBP2 activation and cholesterolgenesis. Importantly, α-syn aggregate accumulation and other effects caused by nutrient deprivation were counteracted by knockdown of SREBP2, treatment with cholesterol lowering agent—lovastatin, or by GRP78 overexpression, which also caused decrease of SREBP2 activity. Similar results were obtained from studies of primary neurons with α-syn overexpression under nutrient deprivation. Together our findings suggested that down-regulation of SREBP2 activity might be a means to prevent α-syn aggregation in PD via reducing cholesterol levels
    Full-text · Article · Oct 2014
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