α-Synuclein amino terminus regulates mitochondrial membrane permeability

Shen, Jingjing; Du, Tingting; Wang, Xue; Duan, Chaojun; Gao, Ge; Zhang, Jianliang; Lu, Lingling; Yang, Hui

doi:10.1016/j.brainres.2014.09.046

Cited by 72 publications

(62 citation statements)

References 48 publications

(59 reference statements)

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“…Mitochondrial dysfunction associated with α‐syn has been suggested to be specifically regulated by the N‐terminal region of the protein (Shen et al . ).…”

Section: α‐Syn Toxicitymentioning

confidence: 97%

“…Contrarily, experiments in a synucleinopathy animal model could not show a correlation between a-syn pathology and complex I inhibition, suggesting the latter could be more related to the physiological role of a-syn (Loeb et al 2010). Other proposed mechanisms by which a-syn can affect mitochondria include disruption and fragmentation of mitochondria morphology and dynamics, alteration of mitochondrial membrane permeability and potential, increase in mitochondrial Reactive Oxygen Species levels and defects in mitochondria macroautophagy (Nakamura et al 2011;Xie and Chung 2012;Sarafian et al 2013;Plotegher et al 2014;Shen et al 2014;Chen et al 2015). Mitochondrial dysfunction associated with a-syn has been suggested to be specifically regulated by the N-terminal region of the protein (Shen et al 2014).…”

Section: A-syn Alters Mitochondrial Functionmentioning

confidence: 99%

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Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

Villar‐Piqué

Fonseca

Outeiro

2015

Journal of Neurochemistry

184

161

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Parkinson's disease belongs to a group of currently incurable neurodegenerative disorders characterized by the misfolding and accumulation of alpha-synuclein aggregates that are commonly known as synucleinopathies. Clinically, synucleinopathies are heterogeneous, reflecting the somewhat selective neuronal vulnerability characteristic of each disease. The precise molecular underpinnings of synucleinopathies remain unclear, but the process of aggregation of alpha-synuclein appears as a central event. However, there is still no consensus with respect to the toxic forms of alpha-synuclein, hampering our ability to use the protein as a target for therapeutic intervention. To decipher the molecular bases of synucleinopathies, it is essential to understand the complex triangle formed between the structure, function and toxicity of alpha-synuclein. Recently, important steps have been undertaken to elucidate the role of the protein in both physiological and pathological conditions. Here, we provide an overview of recent findings in the field of alpha-synuclein research, and put forward a new perspective over paradigms that persist in the field. Establishing whether alpha-synuclein has a causative role in all synucleinopathies will enable the identification of targets for the development of novel therapeutic strategies for this devastating group of disorders.

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“…Mitochondrial dysfunction associated with α‐syn has been suggested to be specifically regulated by the N‐terminal region of the protein (Shen et al . ).…”

Section: α‐Syn Toxicitymentioning

confidence: 97%

Section: A-syn Alters Mitochondrial Functionmentioning

confidence: 99%

Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

Villar‐Piqué

Fonseca

Outeiro

2015

Journal of Neurochemistry

184

161

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“…Alterations in the cardiolipin content or composition of brain may have pathological consequences . Decreases in the total cardiolipin content of brain mitochondria have been reported in Parkinson's Disease , Alzheimer's Disease , and in age‐related dementia . Changes in the fatty acyl composition of brain cardiolipin are also reported.…”

Section: Tissue‐specific Molecular Cardiolipin Compositionmentioning

confidence: 99%

Influence of tissue, diet, and enzymatic remodeling on cardiolipin fatty acyl profile

Bradley

Duncan

2016

Molecular Nutrition Food Res

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Cardiolipin is a specialized phospholipid found primarily in the inner mitochondrial membrane. Because of its unique dimeric structure, cardiolipin plays an important role in mitochondrial function, stability, and membrane fluidity. As such, cardiolipin is subject to a high degree of remodeling by phospholipases, acyltransferases, and transacylases that create a fatty acyl profile that tends to be highly tissue-specific. Despite this overarching regulation, the molecular species of cardiolipin produced are also influenced by dietary lipid composition. A number of studies have characterized the tissue-specific profile of cardiolipin species and have investigated the specific nature of cardiolipin remodeling, including the role of both enzymes and diet. The aim of this review is to highlight tissue specific differences in cardiolipin composition and, collectively, the enzymatic and dietary factors that contribute to these differences. Consequences of aberrant cardiolipin fatty acyl remodeling are also discussed.

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“…This study suggests that α-synuclein translocate to the mitochondria via porin to target complexes of the mitochondrial respiratory chain. The accumulation and aggregation of abnormal α-synuclein was shown to down-regulate porin [14] and possibly regulate mitochondrial permeability [15]. The association between the PD gene α-synuclein and the mitochondrial channel porin appears to be important in the progression of PD.…”

Section: Introductionmentioning

confidence: 99%

Loss of porin function in dopaminergic neurons of Drosophila is suppressed by Buffy

M’Angale

Staveley

2016

J Biomed Sci

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BackgroundMitochondrial porin, also known as the voltage-dependent anion channel (VDAC), is a multi-functional channel protein that shuttles metabolites between the mitochondria and the cytosol and implicated in cellular life and death decisions. The inhibition of porin under the control of neuronal Ddc-Gal4 result in short lifespan and in an age-dependent loss in locomotor function, phenotypes that are strongly associated with Drosophila models of Parkinson disease.MethodsLoss of porin function was achieved through exploitation of RNA interference while derivative lines were generated by homologous recombination and tested by PCR. The UAS/Gal4 expression system was exploited with directed expression in neurons achieved with the use of the Dopa decarboxylase and in the developing eye with the Glass multiple reporter transgenes. Statistical analyses for ageing assay employed Log rank (Mantel-Cox) test, climbing indices were fitted with a non-linear curve and confidence intervals compared at 95%. Biometric analysis of the eye phenotypes was obtained by unpaired student T-test.ResultsThe expression of α-synuclein in neuronal populations that include dopamine producing neurons under the control of Ddc-Gal4 produces a robust Parkinson disease model, and results in severely reduced lifespan and locomotor dysfunction. In addition, the porin-induced phenotypes are greatly suppressed when the pro-survival Bcl-2 homologue Buffy is overexpressed in these neurons and in the developing eye adding to the cellular advantages of altered expression of this anti-apoptotic gene. When we co-expressed α-synuclein along with porin, it results in a decrease in lifespan and impaired climbing ability. This enhancement of the α-synuclein-induced phenotypes observed in neurons was demonstrated in the neuron rich eye, where the simultaneous co-expression of porin-RNAi and α-synuclein resulted in an enhanced eye phenotype, marked by reduced number of ommatidia and increased disarray of the ommatidia.ConclusionsThe inhibition of porin in dopaminergic neurons among others result in reduced lifespan and age-dependent loss in climbing ability, phenotypes that are suppressed by the overexpression of the sole pro-survival Bcl-2 homologue Buffy. The inhibition of porin phenocopies Parkinson disease phenotypes in Drosophila, while the overexpression of Buffy can counteract these phenotypes to improve the overall “healthspan” of the organism.

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α-Synuclein amino terminus regulates mitochondrial membrane permeability

Cited by 72 publications

References 48 publications

Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

Influence of tissue, diet, and enzymatic remodeling on cardiolipin fatty acyl profile

Loss of porin function in dopaminergic neurons of Drosophila is suppressed by Buffy

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