Loss of dopaminergic cells induced by alpha-synuclein accumulation in substantia nigra causes the development of Parkinson's disease (PD). To date, although autophagy has been implicated in the pathology of PD, the molecular mechanism is still unclear. To study the role of autophagy in PD pathogenesis, we established stable SH-SY5Y cell lines overexpressing wild-type or mutant alpha-synuclein proteins (A30P or A53T). Overexpression of mutant alpha-synuclein induced some protein aggregates and cell death in the absence of drug. LC3-II protein, a critical marker for autophagy, was produced in an autophagy-dependent manner. The rotenone-induced cell death was interrupted by autophagy stimulation. Autophagy activation also restored the mitochondrial membrane potential (MMP) impaired by rotenone in mutant alpha-synuclein expressing cells. Additionally, autophagy activation significantly relieved rotenone-induced ROS accumulation and HIF-1alpha expression in neuronal cells expressing mutant alpha-synuclein proteins. These findings indicate that autophagy plays an important scavenger role against harmful influence of toxic protein aggregates produced in rotenone-treated cells.
"Basal expression of autophagy acts as one of the cytoprotective mechanisms and participates in maintaining homeostasis (Hara et al., 2006; Dadakhujaev et al., 2010). Also in diseased conditions, autophagy enhancement is known to play a role as protective mechanism. "
[Show abstract][Hide abstract] 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
"Recent studies have implicated macroautophagy, from here on referred to as " autophagy " , in the pathophysiology of PD (Lynch- Day et al., 2012). Still, there is an ongoing debate if alpha-synuclein itself would inhibit (Winslow and Rubinsztein, 2011; Winslow et al., 2010) or activate autophagy (Choubey et al., 2011; Stefanis et al., 2001; Xilouri et al., 2009) and whether increased autophagy would be protective (Dadakhujaev et al., 2010; Spencer et al., 2009) or harmful (Choubey et al., 2011; Li et al., 2011) for neurons. We report here that wild-type alpha-synuclein readily kills the human postmitotic dopaminergic neurons derived from primary precursor cells, and that pharmacologic activation of autophagy with trifluoperazine (10-[3-(4-methylpiperazin-1-yl) propyl]-2- (trifluoromethyl) phenothiazine) provides protection by reducing one specific oligomeric alpha-synuclein species. "
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Presently, there is no causal therapy available to slow down or halt disease progression. The presynaptic protein alpha-synuclein aggregates to form intraneuronal Lewy bodies in PD. It is generally believed that intermediates on the way from monomers to the large aggregates would mediate neurotoxicity, but the precise species and mechanism responsible for neuronal death are controversially debated. To study alpha-synuclein-mediated toxicity, we developed a new model in which moderate overexpression of wild-type alpha-synuclein led to gradual death of human postmitotic dopaminergic neurons. In accordance with findings in postmortem PD brains, small oligomeric species occurred and the autophagic flux was impaired in our model. The phenothiazine neuroleptic trifluoperazine, an activator of macroautophagy, selectively reduced one particular alpha-synuclein species and rescued cells. Inversely, blocking of autophagy led to an accumulation of this oligomeric species and increased cell death. These data show that activation of autophagy is a promising approach to protect against alpha-synuclein pathology and likely acts by targeting one specific alpha-synuclein species.
Neurobiology of aging 01/2014; 35(7). DOI:10.1016/j.neurobiolaging.2014.01.027 · 5.01 Impact Factor
"Transfection of the common G2019S LRRK2 mutation into SH-SY5Y cells was reported to increase autophagy in both neuritic and somatic compartments . Autophagy activation was observed to restore the mitochondrial membrane potential impaired by rotenone in SH-SY5Y cell lines overexpressing α-synuclein  and attenuate rotenone-induced toxicity in SH-SY5Y cell lines . "
[Show abstract][Hide abstract] ABSTRACT: The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction,
-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxic
-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i) the formation of
-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii) the formation of adducts with
-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.
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