Pan, T., Kondo, S., Le, W. & Jankovic, J. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease. Brain 131, 1969-1978

Parkinson's Disease Research Laboratory, Baylor College of Medicine, Houston, TX 77030, USA.
Brain (Impact Factor: 9.2). 02/2008; 131(Pt 8):1969-78. DOI: 10.1093/brain/awm318
Source: PubMed


The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two most important mechanisms that normally repair or remove abnormal proteins. Alterations in the function of these systems to degrade misfolded and aggregated proteins are being increasingly recognized as playing a pivotal role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease. Dysfunction of the UPS has been already strongly implicated in the pathogenesis of this disease and, more recently, growing interest has been shown in identifying the role of ALP in neurodegeneration. Mutations of alpha-synuclein and the increase of intracellular concentrations of non-mutant alpha-synuclein have been associated with Parkinson's disease phenotype. The demonstration that alpha-synuclein is degraded by both proteasome and autophagy indicates a possible linkage between the dysfunction of the UPS or ALP and the occurrence of this disorder. The fact that mutant alpha-synucleins inhibit ALP functioning by tightly binding to the receptor on the lysosomal membrane for autophagy pathway further supports the assumption that impairment of the ALP may be related to the development of Parkinson's disease. In this review, we summarize the recent findings related to this topic and discuss the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP enhancement.

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Available from: Joseph Jankovic, Mar 29, 2015
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    • "Indeed, the Cu/Zn superoxide dismutase 1 G93A mutant forms large cytoplasmic aggregates in NSC34 cells. Increased autophagic structures have been found in neurons affected by neurodegenerative disease caused by aggregation-prone proteins[3940]. "
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    ABSTRACT: Previous studies have confirmed that the beclin 1 complex plays a key role in the initial stage of autophagy and deregulated autophagy might involve in amyotrophic lateral sclerosis. However, the mechanism underlying altered autophagy associated with the beclin 1 complex remains unclear. In this study, we transfected the Cu/Zn superoxide dismutase 1 G93A mutant protein into the motor neuron-like cell line NSC34 cultured in vitro. Western blotting and co-immunoprecipitation showed that the Cu/Zn superoxide dismutase 1 G93A mutant enhanced the turnover of autophagic marker microtubule-associated protein light chain 3II (LC3II) and stimulated the conversion of EGFP-LC3I to EGFP-LC3II, but had little influence on the binding capacity of the autophagy modulators ATG14L, rubicon, UVRAG, and hVps34 to beclin 1 during autophagosome formation. These results suggest that the amyotrophic lateral sclerosis-linked Cu/Zn superoxide dismutase 1 G93A mutant can upregulate autophagic activity in NSC34 cells, but that this does not markedly affect beclin 1 complex components.
    Neural Regeneration Research 09/2014; 9(1):16-24. DOI:10.4103/1673-5374.125325 · 0.22 Impact Factor
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    • "As known, Parkinson's disease (PD) is resulted by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of midbrain (Bae et al., 2011). Preventing aggregated and misfolded proteins in brain blocked the progression of PD which may propose a potential therapeutic benefi t (Pan et al., 2008a; Bae et al., 2011). Recently, the ubiquitin-proteasome system and the autophagy-lysosomal pathway are the two most important cellular mechanisms for protein degradation (Pan et al., 2008b). "
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    ABSTRACT: Autophagy is a series of catabolic process mediating the bulk degradation of intracellular proteins and organelles through formation of a double-membrane vesicle, known as an autophagosome, and fusing with lysosome. Autophagy plays an important role of death-survival decisions in neuronal cells, which may influence to several neurodegenerative disorders including Parkinson's disease. Chebulagic acid, the major constituent of Terminalia chebula and Phyllanthus emblica, is a benzopyran tannin compound with various kinds of beneficial effects. This study was performed to investigate the autophagy enhancing effect of chebulagic acid on human neuroblastoma SH-SY5Y cell lines. We determined the effect of chebulagic acid on expression levels of autophago-some marker proteins such as, DOR/TP53INP2, Golgi-associated ATPase Enhancer of 16 kDa (GATE 16) and Light chain 3 II (LC3 II), as well as those of its upstream pathway proteins, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and Beclin-1. All of those proteins were modulated by chebulagic acid treatment in a way of enhancing the autophagy. Additionally in our study, chebulagic acid also showed a protective effect against 1-methyl-4-phenylpyridinium (MPP(+)) - induced cytotoxicity which mimics the pathological symptom of Parkinson's disease. This effect seems partially mediated by enhanced autophagy which increased the degradation of aggregated or misfolded proteins from cells. This study suggests that chebulagic acid is an attractive candidate as an autophagy-enhancing agent and therefore, it may provide a promising strategy to prevent or cure the diseases caused by accumulation of abnormal proteins including Parkinson's disease.
    Biomolecules and Therapeutics 07/2014; 22(4):275-81. DOI:10.4062/biomolther.2014.068 · 1.73 Impact Factor
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    • "Recently, more attentions have been given to the association between autophagy and excitotoxicity. Excessive autophagy may promote cell death through release of lysosomal enzymes and other factors [11]. However, autophagy on other hand is proved to be a ubiquitous cytoprotective process by selectively removing damaged mitochondria [12]. "
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    ABSTRACT: The neuroprotective activity of pyruvate has been confirmed in previous in vivo and in vitro studies. Here, we report a novel mechanism that pyruvate prevents SH-SY5Y cells from glutamate excitotoxicity by regulating death-associated protein kinase 1 (DAPK1) protein complex. Our results showed pyruvate regulated DAPK1 protein complex to protect cells by two ways. First, pyruvate induced the dissociation of DAPK1 with NMDA receptors. The disruption of the DAPK1-NMDA receptors complex resulted in a decrease in NMDA receptors phosphorylation. Then the glutamate-stimulated Ca2+ influx was inhibited and intracellular Ca2+ overload was alleviated, which blocked the release of cytochrome c and cell death. In addition, increased Bcl-xL induced by pyruvate regulated Bax/Bak dependent death by inhibiting the release of cytochrome c from the mitochondrial inter-membrane space into the cytosol. As a result, the cytochrome c-initiated caspase cascade, including caspase-3 and caspase-9, was inhibited. Second, pyruvate promoted the association between DAPK1 and Beclin-1, which resulted in autophagy activation. The autophagy inhibitor 3-methyladenine reversed the protection afforded by pyruvate. Furthermore, the attenuation of mitochondrial damage induced by pyruvate was partly reduced by 3-methyladenine. This suggested autophagy mediated pyruvate protection by preventing mitochondrial damage. Taken together, pyruvate protects cells from glutamate excitotoxicity by regulating DAPK1 complexes, both through dissociation of DAPK1 from NMDA receptors and association of DAPK1 with Beclin-1. They go forward to protect cells by attenuating Ca2+ overload and activating autophagy. Finally, a convergence of the two ways protects mitochondria from glutamate excitotoxicity, which leads to cell survival.
    PLoS ONE 04/2014; 9(4):e95777. DOI:10.1371/journal.pone.0095777 · 3.23 Impact Factor
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