α-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease

Rostovtseva, Tatiana K.; Gurnev, Philip A.; Protchenko, Olga; Hoogerheide, David P.; Yap, Thai Leong; Philpott, Caroline C.; Lee, Jennifer C.; Bezrukov, Sergey M.

doi:10.1074/jbc.m115.641746

Cited by 169 publications

(205 citation statements)

References 77 publications

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“…It was recently reported that in addition to tubulin, another abundant cytosolic protein, a neuronal intrinsically disordered α-synuclein involved in etiology of Parkinson disease (PD), effectively blocks VDAC [139]. Rostovtseva et al [139] have shown that monomeric α-synuclein not only reversibly blocks VDAC conductance, similarly to what has been shown to tubulin, but also is able to translocate through the VDAC pore. Experiments with yeast model of PD supported electrophysiological results by demonstrating that VDAC is indeed required for α-synuclein toxicity in yeast.…”

Section: Unsolved Problems In Vdac Structure and Functionmentioning

confidence: 99%

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

Noskov

Rostovtseva

Chamberlin

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane provides a controlled pathway for respiratory metabolites in and out of the mitochondria. In spite of the wealth of experimental data from structural, biochemical, and biophysical investigations, the exact mechanisms governing selective ion and metabolite transport, especially the role of titratable charged residues and interactions with soluble cytosolic proteins, remain hotly debated in the field. The computational advances hold a promise to provide a much sought-after solution to many of the scientific disputes around solute and ion transport through VDAC and hence, across the mitochondrial outer membrane. In this review, we examine how Molecular Dynamics, Free Energy, and Brownian Dynamics simulations of the large β-barrel channel, VDAC, advanced our understanding. We will provide a short overview of non-conventional techniques and also discuss examples of how the modeling excursions into VDAC biophysics prospectively aid experimental efforts.

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Section: Unsolved Problems In Vdac Structure and Functionmentioning

confidence: 99%

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

Noskov

Rostovtseva

Chamberlin

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…At higher potentials VDAC exhibits lower conductance and cation-selective states called closed states. However, the channel behavior of reconstituted VDAC is not the same as that of native one located in the mitochondrial outer membrane as several endogenous factors were indicated to modulate VDAC activity, including NADH [63], Ca 2+ [36], tubulin [64,65], tBid [66] and other members of Bcl-2 protein family [67], hexokinase I and II [36], α-synuclein [68], 18 kDa Translocator protein (TSPO) [69,70] as well as mitochondrial lipids [71] and still unidentified cytoplasmic and mitochondrial proteins [72]. As summarized by [73], VDAC interactions with different proteins contribute to apoptosis, cytoskeleton functions, Ca 2+ and oxidative-redox homeostasis as well as energy transformation (Figure 2).…”

Section: Vdac As a Versatile Proteinmentioning

confidence: 99%

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Karachitos¹,

Grobys²

2015

Pharmaceut Reg Affairs

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It is becoming increasingly evident that mitochondria dysfunction plays an important role in pathogenesis of Huntington's disease (HD). However, the underlying mechanism is still needs to be explained. The crucial aspect of the explanation is to indicate the upstream events in mitochondria dysfunction that could contribute to HD. In the review we propose the defect of voltage-dependent anion-selective channel (VDAC), as a causative event in HDrelated mitochondria dysfunction. Thus, we propose to consider VDAC as a crucial element in HD etiology and consequently as a reasonable target for therapeutic interventions in HD, based on developing novel therapeutic strategies eliminating mitochondria dysfunction.Keywords: Huntington's disease; VDAC; Mitochondria; Therapy Huntington's DiseaseHuntington's disease (HD) is a progressive and fatal neurodegenerative disease with a prevalence of about 5-10/100 000. Clinically, the disease is characterized by progressive chorea (involuntary dance-like movements), rigidity, weight loss, dementia, seizures and psychiatric disturbances such as depression, withdrawal and irritability. These symptoms including cognitive deterioration, psychiatric disturbances, and movement disorders result from a selective and continuous loss of neurons from the striatum and deep layers of the cerebral cortex although other brain regions such as thalamus and subthalamic nucleus are also affected [1][2][3]. Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al. [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades. Thus, a new therapeutic approach involving new potential targets and to start before the symptomatic stage could contribute to HD treatment to be more specific and effective. This, in turn, requires further studies concerning molecular mechanisms underlying HD.The genetic hallmark of HD is an expansion of an unstable trinucleotide CAG repeat region within the first exon of the gene encoding the protein Huntington (Htt). This results in synthesis of its mutant form (mHtt) containing more than 36 glutamine residues at N terminus although the possible contribution of mHtt encoding mRNA, i.e. toxic mRNA in HD etiology has also been suggested [7]. HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12]. Importantly, Htt expression in diffe...

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“…Intravesicular pH drops along the endocytic pathway to ϳ6 and in late endosomes and lysosomes to as low as 4.5 (25,27). In addition to its role in vesicular fusion and trafficking, ␣S is subject to lysosomal degradation (28), and it may enter the slightly alkaline mitochondrial environment (29). Furthermore, pH dysregulation accompanying oxidative stress can result in cytosolic acidification (30), and oxidative stress is a significant contributor to PD pathology (31).…”

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confidence: 99%

A pH-dependent switch promotes β-synuclein fibril formation via glutamate residues

Moriarty

Olson

Atieh

et al. 2017

Journal of Biological Chemistry

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Edited by Wolfgang Peti ␣-Synuclein (␣S) is the primary protein associated with Parkinson's disease, and it undergoes aggregation from its intrinsically disordered monomeric form to a cross-␤ fibrillar form. The closely related homolog ␤-synuclein (␤S) is essentially fibril-resistant under cytoplasmic physiological conditions. Toxic gain-of-function by ␤S has been linked to dysfunction, but the aggregation behavior of ␤S under altered pH is not wellunderstood. In this work, we compare fibril formation of ␣S and ␤S at pH 7.3 and mildly acidic pH 5.8, and we demonstrate that pH serves as an on/off switch for ␤S fibrillation. Using ␣S/␤S domain-swapped chimera constructs and single residue substitutions in ␤S, we localized the switch to acidic residues in the N-terminal and non-amyloid component domains of ␤S. Computational models of ␤S fibril structures indicate that key glutamate residues (Glu-31 and Glu-61) in these domains may be sites of pH-sensitive interactions, and variants E31A and E61A show dramatically altered pH sensitivity for fibril formation supporting the importance of these charged side chains in fibril formation of ␤S. Our results demonstrate that relatively small changes in pH, which occur frequently in the cytoplasm and in secretory pathways, may induce the formation of ␤S fibrils and suggest a complex role for ␤S in synuclein cellular homeostasis and Parkinson's disease. ␣-Synuclein (␣S),5 the primary protein component of intracytoplasmic inclusions known as Lewy bodies (LB) in Parkinson's disease (PD), is a 140-residue, predominantly monomeric, intrinsically disordered protein (IDP) (1-6). It is abundant in the cytosol but present in many organelles (7,8). The monomers of ␣S can aggregate to soluble oligomers as well as insoluble oligomers and fibrils, which are considered to be associated with the pathogenesis of PD (9). A closely related family member, ␤-synuclein (␤S) that co-localizes with ␣S, has ϳ60% sequence identity with ␣S but has not been detected in LBs of PD patients (10, 11). Instead, it has been proposed that ␤S may delay ␣S fibril formation and ameliorate ␣S toxicity in vivo by inhibiting ␣S aggregation (12-14). Furthermore, despite the high sequence similarity, ␤S itself does not form fibrils in vitro at cytoplasmic pH without facilitating agents (15). However, recent reports highlight a role for a possible toxic gain-of-function of ␤S in two different model systems (16,17), and ␤S is a component of vesicle-like lesions in the hippocampus, whose formation accompanies dementia in PD (18). In addition, two ␤S mutations, V70M and P123H, were found in sporadic and familial dementia with LBs and have been suggested to be involved in lysosomal pathology (19 -21). There is an emerging role for ␤S in the pathophysiology of PD, but the molecular determinants of this role remain poorly studied.Understanding the complex relationship of synucleins with neurodegeneration requires consideration of their structures and functions in diverse subcellular environments, beyond the cytoplasm. Altho...

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α-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease

Cited by 169 publications

References 77 publications

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

A pH-dependent switch promotes β-synuclein fibril formation via glutamate residues

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