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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    • "Putative single gene disorders of the autophagy pathway provide a 'genetic window' into the role of autophagy in humans and will inform our understanding of this fascinating pathway and its implications for neurobiology and disease. The latter is particularly important, given that dysregulated autophagy has been implicated in many other inherited and sporadic diseases, including neurodegenerative and neurodevelopmental diseases (Pan et al., 2008a; Ebrahimi-Fakhari et al., 2012, 2014; Nixon, 2013; Ebrahimi-Fakhari and Sahin, 2015), myopathies (Ravenscroft et al., 2015), cardiovascular diseases (Lavandero et al., 2013), cancer (Galluzzi et al., 2015), infectious diseases (Huang and Brumell, 2014), and metabolic diseases (Christian et al., 2013), all of which also affect the CNS. We herein discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six monogenic diseases of autophagy that affect the brain (Table 1). "
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    ABSTRACT: Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain mal- formations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neuro- metabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss ‘congenital dis- orders of autophagy’ as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of heredi- tary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy- related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.
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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.
    No preview · Article · Sep 2014 · Neural Regeneration Research
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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.
    Full-text · Article · Jul 2014 · Biomolecules and Therapeutics
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