Molecular Crowding Accelerates Fibrillization of α-Synuclein:  Could an Increase in the Cytoplasmic Protein Concentration Induce Parkinson's Disease?

Shtilerman, Mark D.; Ding, Tomas T.; Lansbury, Peter T.

doi:10.1021/bi0120906

Cited by 288 publications

(223 citation statements)

References 61 publications

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“…The incremental aggregation process of ␣-synuclein involves several modifications (misfolding, dimer and oligomer formation, and self-aggregation) and is linked to Parkinson's disease-associated mutations (5,22,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). In this study, we detected abnormal ␣-synuclein species based on their detergent solubility and electrophoretic mobility characteristics in three different systems: human DLB cortex, transgenic mice overexpressing wild type human ␣-synuclein, and a transiently transfected cell culture system.…”

Section: Discussionmentioning

confidence: 95%

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Klucken

Shin

Masliah

et al. 2004

Journal of Biological Chemistry

482

400

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Aggregation and cytotoxicity of misfolded ␣-synuclein is postulated to be crucial in the disease process of neurodegenerative disorders such as Parkinson's disease and DLB (dementia with Lewy bodies). In this study, we detected misfolded and aggregated ␣-synuclein in a Triton X-100 insoluble fraction as well as a high molecular weight product by gel electrophoresis of temporal neocortex from DLB patients but not from controls. We also found similar Triton X-100 insoluble forms of ␣-synuclein in an ␣-synuclein transgenic mouse model and in an in vitro model of ␣-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding ␣-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble ␣-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble ␣-synuclein species and protected cells from ␣-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated ␣-synuclein species in vivo and in vitro and protect it from ␣-synuclein-dependent toxicity.␣-Synuclein is a natively unfolded molecule that can selfaggregate to form oligomers and fibrillar intermediates (1-5) that accumulate to form Lewy bodies (LBs) 1 and Lewy neurites in neurons at risk for degeneration in Parkinson's disease and dementia with Lewy bodies (DLB) (6 -14). For the most part, these ␣-synuclein aggregates are densely compact and can be immunostained for multiple additional components including ubiquitin, synphilin-1, and heat shock proteins (HSPs), which suggests that protein misfolding or degradation is altered in cells that develop LBs. Mouse models of ␣-synuclein aggregation exist that mimic the findings in human brains and show intracellular ␣-synuclein aggregates (15-17). Aggregated ␣-synuclein molecules are less detergent-soluble, and these detergent-insoluble species of ␣-synuclein can be detected in human brain, transgenic mouse models, and in vitro models (18 -21). Although it is known that the conformation of ␣-synuclein in LBs is significantly different from that in the neuropil (22), it is unclear which conformation of ␣-synuclein contributes to inclusion formation. In addition to the formation of intracellular aggregates, ␣-synuclein is also cytotoxic. It has been postulated that ␣-synuclein oligomers found in Parkinson's disease tissue by Western blot analysis represent the toxic species (5).HSPs belong to the family of chaperone proteins and are important in both refolding misfolded proteins and directing proteins toward proteasomal degradation (23-25). HSPs can be protective in several neurodegeneration models (26 -29), and recent data in the fly model suggest that overexpression of the molecular chaperone Hsp70 protects against ␣-synuclein-induced degeneration (26, 30). Hsp70 and its related co-chaperones may be important in ␣-synuclein misfolding. In fact, sever...

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Section: Discussionmentioning

confidence: 95%

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Klucken

Shin

Masliah

et al. 2004

Journal of Biological Chemistry

482

400

View full text Add to dashboard Cite

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“…Any model for pathogenesis must explain these cases. It is important to emphasize that the wild-type proteins will also form amyloid pores in vitro, albeit more reluctantly than the disease-associated mutants (Hafner et al 2001;Ding et al 2002 ;Lashuel et al 2002aLashuel et al , b, 2003Shtilerman et al 2002 ;Chromy et al 2003 ;Chung, 2003 ;Klug et al 2003 ;. Factors other than mutations could trigger pore formation pathogenesis in sporadic disease (Fig.…”

Section: Mechanisms Of Protofibril Induced Toxicity In Protein Aggregmentioning

confidence: 99%

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Lashuel

Lansbury

2006

Quart. Rev. Biophys.

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381

368

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Abstract. Protein fibrillization is implicated in the pathogenesis of most, if not all, ageassociated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ' amyloid pore'. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

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“…15−18 In line with this concept, it has been proposed that changes in α-Syn homeostasis upon aging result in an apparent increase of the cellular α-Syn concentration. This may include, for instance, alterations in the molecular crowding state due to cell shrinkage 2,19 or a breakdown of the α-Syn degradation mechanism. 20,21 Recent studies highlighted the enhanced aggregation propensity of α-Syn in the presence of interfaces such as lipid bilayers 22,23 or suggest a surface-assisted nucleation mechanism.…”

mentioning

confidence: 99%

On-Surface Aggregation of α-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms

Rabe

Soragni

Reynolds

et al. 2013

ACS Chem. Neurosci.

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The aggregation of α-synuclein (α-Syn) is believed to be one of the key steps driving the pathology of Parkinson's disease and related neurodegenerative disorders. One of the present hypotheses is that the onset of such pathologies is related to the rise of α-Syn levels above a critical concentration at which toxic oligomers or mature fibrils are formed. In the present study, we find that α-Syn aggregation in vitro is a spontaneous process arising at bulk concentrations as low as 1 nM and below in the presence of both hydrophilic glass surfaces and cell membrane mimicking supported lipid bilayers (SLBs). Using three-dimensional supercritical angle fluorescence (3D-SAF) microscopy, we observed the process of α-Syn aggregation in situ. As soon as α-Syn monomers were exposed to the surface, they started to adsorb and aggregate along the surface plane without a prior lag phase. However, at a later stage of the aggregation process, a second type of aggregate was observed. In contrast to the first type, these aggregates showed an extended structure being tethered with one end to the surface and being mobile at the other end, which protruded into the solution. While both types of α-Syn aggregates were found to contain amyloid structures, their growing mechanisms turned out to be significantly different. Given the clear evidence that surface-induced α-Syn aggregation in vitro can be triggered at bulk concentrations far below physiological concentrations, the concept of a critical concentration initiating aggregation in vivo needs to be reconsidered.

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Molecular Crowding Accelerates Fibrillization of α-Synuclein: Could an Increase in the Cytoplasmic Protein Concentration Induce Parkinson's Disease?

Cited by 288 publications

References 61 publications

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

On-Surface Aggregation of α-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms

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