The Molecular Chaperone Hsp90 Modulates Intermediate Steps of Amyloid Assembly of the Parkinson-related Protein α-Synuclein

Falsone, S. Fabio; Kungl, Andreas J.; Rek, Angelika; Cappai, Roberto; Zangger, Klaus

doi:10.1074/jbc.m109.057240

Cited by 113 publications

(90 citation statements)

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“…Molecular chaperones exert critical housekeeping functions in vivo including refolding, maintaining proteins in a soluble state, and/or pacifying protein aggregates (8). Hsp90, for example, modulates ␣-Syn assembly (38). The inducible molecular chaperone, Hsp70, has been previously shown to inhibit ␣-Syn assembly into fibrils (11,15).…”

Section: Discussionmentioning

confidence: 99%

Hsc70 Protein Interaction with Soluble and Fibrillar α-Synuclein

Pemberton

Madiona

Pieri

et al. 2011

Journal of Biological Chemistry

100

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The aggregation of ␣-synuclein (␣-Syn), the primary component of Lewy bodies, into high molecular weight assemblies is strongly associated with Parkinson disease. This event is believed to result from a conformational change within native ␣-Syn. Molecular chaperones exert critical housekeeping functions in vivo including refolding, maintaining in a soluble state, and/or pacifying protein aggregates. The influence of the stressinduced heat shock protein 70 (Hsp70) on ␣-Syn aggregation has been notably investigated. The constitutively expressed chaperone Hsc70 acts as an antiaggregation barrier before cells are overwhelmed with ␣-Syn aggregates and Hsp70 expression induced. Here, we investigate the interaction between Hsc70 and ␣-Syn, the consequences of this interaction, and the role of nucleotides and co-chaperones Hdj1 and Hdj2 as modulators. We show that Hsc70 sequesters soluble ␣-Syn in an assembly incompetent complex in the absence of ATP. The affinity of Hsc70 for soluble ␣-Syn diminishes upon addition of ATP alone or together with its co-chaperones Hdj1 or Hdj2 allowing faster binding and release of client proteins thus abolishing ␣-Syn assembly inhibition by Hsc70. We show that Hsc70 binds ␣-Syn fibrils with a 5-fold tighter affinity compared with soluble ␣-Syn. This suggests that Hsc70 preferentially interacts with high molecular weight ␣-Syn assemblies in vivo. Hsc70 binding certainly has an impact on the physicochemical properties of ␣-Syn assemblies. We show a reduced cellular toxicity of ␣-Syn fibrils coated with Hsc70 compared with "naked" fibrils. Hsc70 may therefore significantly affect the cellular propagation of ␣-Syn aggregates and their spread throughout the central nervous system in Parkinson disease.2 is one of the principal components of intracellular Lewy bodies, whose presence in the central nervous system is a defining feature of Parkinson disease (PD) and other synucleinopathies (1). Symptoms of PD are apparent after more than 70% of dopaminergic terminals and/or neurons have been lost, with some of the remaining neurons containing filamentous ␣-Syn. The precise cellular function of soluble ␣-Syn is unknown. There is, however, evidence that it plays an important role at presynaptic termini (2-4) and it has recently been suggested that the protein is a cellular ferrireductase (5). Various factors, including genetic susceptibility and environmental influences, can induce the aggregation of the naturally unfolded, soluble ␣-Syn (6, 7), leading to PD pathogenesis.Molecular chaperones assist newly synthesized proteins to reach their native-fold and are in charge of refolding misfolded or unfolded proteins (8). As the progression of PD is strongly associated with a change in ␣-Syn solubility, which is widely believed to be the consequence of a conformational change, there has been significant focus on the possible therapeutic role of molecular chaperones in the past 5 years (9). Previous investigations have focused on heat shock protein 70 (Hsp70) (10 -13), a molecular chaperone whose express...

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Section: Discussionmentioning

confidence: 99%

Hsc70 Protein Interaction with Soluble and Fibrillar α-Synuclein

Pemberton

Madiona

Pieri

et al. 2011

Journal of Biological Chemistry

100

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“…Interestingly, although Hsp40 was reported to suppress polyQ aggregation in concert with Hsp70 (Muchowski et al, 2000) and Hsp90 is known to modulate the aggregation of the PD-linked protein -synuclein (Falsone et al, 2009), neither Hsp40 nor Hsp90 colocalized with CsA-PrP aggresomes (supplementary material Fig. S2).…”

Section: Csa-prp Aggresomes Attract Cellular Folding Chaperonesmentioning

confidence: 99%

Cyclosporin-A-induced prion protein aggresomes are dynamic quality-control cellular compartments

Ben‐Gedalya

Lyakhovetsky

Yedidia

et al. 2011

Journal of Cell Science

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SummaryDespite the activity of cellular quality-control mechanisms, subsets of mature and newly synthesized polypeptides fail to fold properly and form insoluble aggregates. In some cases, protein aggregation leads to the development of human neurodegenerative maladies, including Alzheimer's and prion diseases. Aggregates of misfolded prion protein (PrP), which appear in cells after exposure to the drug cyclosporin A (CsA), and disease-linked PrP mutants have been found to accumulate in juxtanuclear deposition sites termed 'aggresomes'. Recently, it was shown that cells can contain at least two types of deposition sites for misfolded proteins: a dynamic quality-control compartment, which was termed 'JUNQ', and a site for terminally aggregated proteins called 'IPOD'. Here, we show that CsA-induced PrP aggresomes are dynamic structures that form despite intact proteasome activity, recruit chaperones and dynamically exchange PrP molecules with the cytosol. These findings define the CsA-PrP aggresome as a JUNQ-like dynamic qualitycontrol compartment that mediates the refolding or degradation of misfolded proteins. Together, our data suggest that the formation of PrP aggresomes protects cells from proteotoxic stress.

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“…Hsp90 is known to work in concert with Hsp70 to maintain proteins such as tau in a soluble and functional conformation (Dou et al 2003) and to inhibit early stages of β-amyloid aggregation (Evans et al 2006). Hsp90 can also inhibit α-synuclein aggregation by interaction with soluble oligomers (Daturpalli et al 2013;Falsone et al 2009). In Parkinson's models, CHIP and Hsp90 both modulate the stability of leucine-rich repeat kinase 2 (LRRK2), a protein in which mutations increase the risk for developing Parkinson's disease (Ding and Goldberg 2009;Hurtado-Lorenzo and Anand 2008;Ko et al 2009;Rudenko et al 2012;Wang et al 2008).…”

Section: Heat Shock Proteins In Neurodegenerative Disorders and Agingmentioning

confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

143

119

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Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stressinduced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

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The Molecular Chaperone Hsp90 Modulates Intermediate Steps of Amyloid Assembly of the Parkinson-related Protein α-Synuclein

Cited by 113 publications

References 50 publications

Hsc70 Protein Interaction with Soluble and Fibrillar α-Synuclein

Hsc70 Protein Interaction with Soluble and Fibrillar α-Synuclein

Cyclosporin-A-induced prion protein aggresomes are dynamic quality-control cellular compartments

Heat shock proteins in neurodegenerative disorders and aging

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