Mechanism of alpha-synuclein oligomerization and membrane interaction: theoretical approach to unstructured proteins studies

Tsigelny, Igor F.; Sharikov, Yuriy; Miller, Mark A.; Masliah, Eliezer

doi:10.1016/j.nano.2008.05.005

Cited by 48 publications

(37 citation statements)

References 27 publications

(41 reference statements)

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“…They are currently limited to the nanosecond to microsecond timescale for continuous MD simulations, depending on the size of the system and the available computational resources. For example, a-synuclein was recently studied using atomistic MD simulations as a monomer in solution and as an aggregate with a membrane (for a total of more than 200 000 atoms) for several nanoseconds (Tsigelny et al 2007;Tsigelny et al 2008).…”

Section: Challenges and Considerationsmentioning

confidence: 99%

Molecular simulations of protein disorderThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

Rauscher

Pomès

2010

Biochem. Cell Biol.

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Protein disorder is abundant in proteomes throughout all kingdoms of life and serves many biologically important roles. Disordered states of proteins are challenging to study experimentally due to their structural heterogeneity and tendency to aggregate. Computer simulations, which are not impeded by these properties, have recently emerged as a useful tool to characterize the conformational ensembles of intrinsically disordered proteins. In this review, we provide a survey of computational studies of protein disorder with an emphasis on the interdisciplinary nature of these studies. The application of simulation techniques to the study of disordered states is described in the context of experimental and bioinformatics approaches. Experimental data can be incorporated into simulations, and simulations can provide predictions for experiment. In this way, simulations have been integrated into the existing methodologies for the study of disordered state ensembles. We provide recent examples of simulations of disordered states from the literature and our own work. Throughout the review, we emphasize important predictions and biophysical understanding made possible through the use of simulations. This review is intended as both an overview and a guide for structural biologists and theoretical biophysicists seeking accurate, atomic-level descriptions of disordered state ensembles.

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Section: Challenges and Considerationsmentioning

confidence: 99%

Molecular simulations of protein disorderThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

Rauscher

Pomès

2010

Biochem. Cell Biol.

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“…Accounting in part for cellular toxicity, small soluble aggregates ofsynuclein, A peptides, Prp Sc or polyglutamine tracts can spontaneously assemble into membrane pores, causing ion leakage [25][26][27]. Failure of the cell to prevent the formation of misfolded proteins, and to rescue or eliminate them, results in the accumulation of intracellular aggregates in the form of stable inclusion bodies in prokaryotes [28] and of inclusion bodies and tangles in animal cells.…”

Section: Protein Misfolding and Aggregation Cause Important Human Dismentioning

confidence: 99%

Disaggregating Chaperones: An Unfolding Story

Sharma¹,

Christen²,

Goloubinoff

2009

CPPS

100

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Stress, molecular crowding and mutations may jeopardize the native folding of proteins. Misfolded and aggregated proteins not only loose their biological activity, but may also disturb protein homeostasis, damage membranes and induce apoptosis. Here, we review the role of molecular chaperones as a network of cellular defenses against the formation of cytotoxic protein aggregates. Chaperones favour the native folding of proteins either as "holdases", sequestering hydrophobic regions in misfolding polypeptides, and/or as "unfoldases", forcibly unfolding and disentangling misfolded polypeptides from aggregates. Whereas in bacteria, plants and fungi Hsp70/40 acts in concert with the Hsp100 (ClpB) unfoldase, Hsp70/40 is the only known chaperone in the cytoplasm of mammalian cells that can forcibly unfold and neutralize cytotoxic protein conformers. Owing to its particular spatial configuration, the bulky 70 kDa Hsp70 molecule, when distally bound through a very tight molecular clamp onto a 50-fold smaller hydrophobic peptide loop extruding from an aggregate, can locally exert on the misfolded segment an unfolding force of entropic origin, thus destroying the misfolded structures that stabilize aggregates. ADP/ATP exchange triggers Hsp70 dissociation from the ensuing enlarged unfolded peptide loop, which is then allowed to spontaneously refold into a closer-to-native conformation devoid of affinity for the chaperone. Driven by ATP, the cooperative action of Hsp70 and its co-chaperone Hsp40 may thus gradually convert toxic misfolded protein substrates with high affinity for the chaperone, into non-toxic, natively refolded, low-affinity products. Stress- and mutation-induced protein damages in the cell, causing degenerative diseases and aging, may thus be effectively counteracted by a powerful network of molecular chaperones and of chaperone-related proteases.

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“…α-Synuclein (α-syn) is a 140 amino acid synaptic protein (Iwai et al, 1995) involved in neurotransmitter release (Liu et al, 2004; Nemani et al, 2010) that accumulates in synaptic terminals (Bellucci et al, 2012; Kramer and Schulz-Schaeffer, 2007; Roy et al, 2007), axons (Dickson et al, 1994; Games et al, 2013), neuronal soma (Spillantini et al, 1997; Takeda et al, 1998), and oligodendrocytes (Papp and Lantos, 1992; Wakabayashi et al, 2000). Under physiological conditions, α-syn is a relatively unstructured monomer (Lashuel et al, 2013; Tsigelny et al, 2007; Tsigelny et al, 2008; Tsigelny et al, 2012) that adopts a β-helical structure when associated with membranes (Ulmer et al, 2005). α-Syn can also adopt a tetramer conformation (Bartels et al, 2011) that is important for vesicular function (Wang et al, 2014) and accumulates as aggregated species (oligomers, protofibrils and fibrils) (Conway et al, 1998; Hashimoto and Masliah, 1999; Iwatsubo et al, 1996; Lansbury, 1999; Lashuel et al, 2013; Oueslati et al, 2010; Taschenberger et al, 2012; Trojanowski et al, 1998; Tsigelny et al, 2008; Winner et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Under physiological conditions, α-syn is a relatively unstructured monomer (Lashuel et al, 2013; Tsigelny et al, 2007; Tsigelny et al, 2008; Tsigelny et al, 2012) that adopts a β-helical structure when associated with membranes (Ulmer et al, 2005). α-Syn can also adopt a tetramer conformation (Bartels et al, 2011) that is important for vesicular function (Wang et al, 2014) and accumulates as aggregated species (oligomers, protofibrils and fibrils) (Conway et al, 1998; Hashimoto and Masliah, 1999; Iwatsubo et al, 1996; Lansbury, 1999; Lashuel et al, 2013; Oueslati et al, 2010; Taschenberger et al, 2012; Trojanowski et al, 1998; Tsigelny et al, 2008; Winner et al, 2011). Aggregated species trigger neurodegeneration and can propagate from neuron-to-neuron and neuron-to-glial cells via prion-like fashion (Lee et al, 2010; Prusiner et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

El-Agnaf

Overk

Rockenstein

et al. 2017

Neurobiology of Disease

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Disorders with progressive accumulation of α-synuclein (α-syn) are a common cause of dementia and parkinsonism in the aging population. Accumulation and propagation of α-syn play a role in the pathogenesis of these disorders. Previous studies have shown that immunization with antibodies that recognize C-terminus of α-syn reduces the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy. These studies employed antibodies that recognize epitopes within monomeric and aggregated α-syn that were generated through active immunization or administered via passive immunization. However, it is possible that more specific effects might be achieved with antibodies recognizing selective species of the α-syn aggregates. In this respect we recently developed antibodies that differentially recognized various oligomers (Syn-O1, -O2, and -O4) and fibrilar (Syn-F1 and -F2) forms of α-syn. For this purpose wild-type α-syn transgenic (line 61) mice were immunized with these 5 different antibodies and neuropathologically and biochemically analyzed to determine which was most effective at reducing α-syn accumulation and related deficits. We found that Syn-O1, -O4 and -F1 antibodies were most effective at reducing accumulation of α-syn oligomers in multiple brain regions and at preventing neurodegeneration. Together this study supports the notion that selective antibodies against α-syn might be suitable for development new treatments for synucleinopathies such as PD and DLB.

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Mechanism of alpha-synuclein oligomerization and membrane interaction: theoretical approach to unstructured proteins studies

Cited by 48 publications

References 27 publications

Disaggregating Chaperones: An Unfolding Story

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

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