Overexpression of Human E46K Mutant α-Synuclein Impairs Macroautophagy via Inactivation of JNK1-Bcl-2 Pathway

Yan, Jiaqing; Yuan, Yu‐He; Gao, Yubin; Huang, Juyang; Ma, Kaili; Gao, Yan; Zhang, Wanqing; Guo, Xiaofeng; Chen, Nai‐Hong

doi:10.1007/s12035-014-8738-1

Cited by 46 publications

(50 citation statements)

References 86 publications

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“…), although it may also inhibit macroautophagy via JNK/Bcl2, an mTOR (mammalian Target Of Rapamycin) independent pathway (Yan et al . ). On the other hand, the expression of the A53E mutant in cells resulted in increased proteolytic activity of the proteasome (Lazaro et al .…”

Section: The Role Of Intracellular Protein Degradation Systems In α‐Smentioning

confidence: 97%

How is alpha‐synuclein cleared from the cell?

Stefanis

Emmanouilidou

Pantazopoulou

et al. 2019

Journal of Neurochemistry

123

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The levels and conformers of alpha‐synuclein are critical in the pathogenesis of Parkinson's Disease and related synucleinopathies. Homeostatic mechanisms in protein degradation and secretion have been identified as regulators of alpha‐synuclein at different stages of its intracellular trafficking and transcellular propagation. Here we review pathways involved in the removal of various forms of alpha‐synuclein from both the intracellular and extracellular environment. Proteasomes and lysosomes are likely to play complementary roles in the removal of intracellular alpha‐synuclein species, in a manner that depends on alpha‐synuclein post‐translational modifications. Extracellular alpha‐synuclein is cleared by extracellular proteolytic enzymes, or taken up by neighboring cells, especially microglia and astrocytes, and degraded within lysosomes. Exosomes, on the other hand, represent a vehicle for egress of excess burden of the intracellular protein, potentially contributing to the transfer of alpha‐synuclein between cells. Dysfunction in any one of these clearance mechanisms, or a combination thereof, may be involved in the initiation or progression of Parkinson's disease, whereas targeting these pathways may offer an opportunity for therapeutic intervention. This article is part of the Special Issue “Synuclein”.

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Section: The Role Of Intracellular Protein Degradation Systems In α‐Smentioning

confidence: 97%

How is alpha‐synuclein cleared from the cell?

Stefanis

Emmanouilidou

Pantazopoulou

et al. 2019

Journal of Neurochemistry

123

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“…; Yan et al . ) following α‐Syn over‐expression in many cell types, suggesting this process as vulnerable to pathology.…”

Section: Cellular Models Of α‐Syn Pathologymentioning

confidence: 99%

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

Marvian

Koss

Aliakbari

et al. 2019

Journal of Neurochemistry

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Alpha‐synuclein (α‐Syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. The protein was first associated with PD just over 20 years ago, when it was found to (i) be a major component of Lewy bodies and (ii) to be also associated with familial forms of PD. The characterization of α‐Syn pathology has been achieved through postmortem studies of human brains. However, the identification of toxic mechanisms associated with α‐Syn was only achieved through the use of experimental models. In vitro models are highly accessible, enable relatively rapid studies, and have been extensively employed to address α‐Syn‐associated neurodegeneration. Given the diversity of models used and the outcomes of the studies, a cumulative and comprehensive perspective emerges as indispensable to pave the way for further investigations. Here, we subdivided in vitro models of α‐Syn pathology into three major types: (i) models simulating α‐Syn fibrillization and the formation of different aggregated structures in vitro, (ii) models based on the intracellular expression of α‐Syn, reporting on pathogenic conditions and cellular dysfunctions induced, and (iii) models using extracellular treatment with α‐Syn aggregated species, reporting on sites of interaction and their downstream consequences. In summary, we review the underlying molecular mechanisms discovered and categorize protective strategies, in order to pave the way for future studies and the identification of effective therapeutic strategies. This article is part of the Special Issue “Synuclein”.

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“…In particular, autophagy inhibition leads to polyubiquitin aggregate accumulation (Rubinsztein, 2006), and certain genetic changes in neurodegenerative disorders identify autophagy genes. For example, the age of onset in Huntington's disease is modified by a polymorphism in autophagy gene ATG7 (Metzger et al, 2010), and an α-synuclein variant that is causal for Parkinson's disease impairs autophagy through beclin 1 inhibition (Yan et al, 2014). Furthermore, autophagy-deficient mouse neurons accumulate polyubiquitin aggregates and exhibit neurodegeneration (Komatsu et al, 2006(Komatsu et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia

Stern

McNew

2016

Journal of Cell Science

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The locomotor deficits in the group of diseases referred to as hereditary spastic paraplegia (HSP) reflect degeneration of upper motor neurons, but the mechanisms underlying this neurodegeneration are unknown. We established a Drosophila model for HSP, atlastin (atl), which encodes an ER fusion protein. Here, we show that neuronal atl loss causes degeneration of specific thoracic muscles that is preceded by other pathologies, including accumulation of aggregates containing polyubiquitin, increased generation of reactive oxygen species and activation of the JNK-Foxo stress response pathway. We show that inhibiting the Tor kinase, either genetically or by administering rapamycin, at least partially reversed many of these pathologies. atl loss from muscle also triggered muscle degeneration and rapamycinsensitive locomotor deficits, as well as polyubiquitin aggregate accumulation. These results indicate that atl loss triggers muscle degeneration both cell autonomously and nonautonomously.

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Overexpression of Human E46K Mutant α-Synuclein Impairs Macroautophagy via Inactivation of JNK1-Bcl-2 Pathway

Cited by 46 publications

References 86 publications

How is alpha‐synuclein cleared from the cell?

How is alpha‐synuclein cleared from the cell?

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia

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