Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex

Scior, Annika; Buntru, Alexander; Arnsburg, Kristin; Ast, Anne; Iburg, Manuel; Juenemann, Katrin; Pigazzini, Maria Lucia; Mlody, Barbara; Puchkov, Dmytro; Priller, Josef; Wanker, Erich E.; Prigione, Alessandro; Kirstein, Janine

doi:10.15252/embj.201797212

Cited by 111 publications

(162 citation statements)

References 49 publications

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“…However, it remains poorly understood to what extent chaperones are capable of disassembling already existing amyloids, given their high thermodynamic stability (Baldwin et al, 2011). Only for α synuclein and HTTExon1Q 48 it has been established that the human Hsp70 machinery is able to disassemble preformed fibrils in vitro (Gao et al, 2015;Scior et al, 2018). Here we investigate the broader role of this machinery in amyloid biology by testing its potential to process aggregates of amyloidogenic Tau isolated from cells or produced in vitro and by characterizing more precisely the products of chaperone-mediated Tau disaggregation.…”

Section: Discussionmentioning

confidence: 99%

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

Nachman

Wentink

Madiona

et al. 2019

Preprint

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The accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease and other Tauopathies. Molecular chaperones are known for their function in maintaining protein homeostasis by preventing the formation or promoting the disaggregation of amorphous and amyloid protein aggregates. Here we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro. This function is mediated by the core chaperone Hsc70, assisted by specific co-chaperones, in particular class B J-domain proteins and an Hsp110-type NEF. Recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell culture were processed by the Hsp70 disaggregation machinery, demonstrating the ability of this machinery to recognize a broad range of Tau aggregates. Chaperone treatment released monomeric, and small oligomeric Tau species, which induced the aggregation of self-propagating Tau species in a Tau cell culture model. We infer from these results that the activity of the Hsp70 disaggregation machinery is a double-sided sword as it attempts to eliminate Tau amyloids but with the price of generating new seeds. The Hsp70 disaggregase therefore has a crucial function in the Tau propagation cycle, rendering it a potential drug target in Tauopathies.

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Section: Discussionmentioning

confidence: 99%

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

Nachman

Wentink

Madiona

et al. 2019

Preprint

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“…Evidence has been provided that molecular chaperones, especially Hsp70 and Hsp40, can prevent formation of amyloid fibers (Muchowski et al 2000) or disaggregate them (Gao et al 2015), showing the potential of modulating the PN to combat proteinopathies in vivo. Accordingly, pharmacological induction or genetic overexpression of molecular chaperones has been shown to prevent aggregation in cellular (Sittler et al 2001) and animal models (Labbadia et al 2012;Kakkar et al 2016;Nagy et al 2016;Scior et al 2018).…”

Section: Ameliorating Proteinopathiesmentioning

confidence: 99%

Functional Modules of the Proteostasis Network

Jayaraj

Hipp

Hartl

2019

Cold Spring Harb Perspect Biol

179

145

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Cells invest in an extensive network of factors to maintain protein homeostasis (proteostasis) and prevent the accumulation of potentially toxic protein aggregates. This proteostasis network (PN) comprises the machineries for the biogenesis, folding, conformational maintenance, and degradation of proteins with molecular chaperones as central coordinators. Here, we review recent progress in understanding the modular architecture of the PN in mammalian cells and how it is modified during cell differentiation. We discuss the capacity and limitations of the PN in maintaining proteome integrity in the face of proteotoxic stresses, such as aggregate formation in neurodegenerative diseases. Finally, we outline various pharmacological interventions to ameliorate proteostasis imbalance.

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“…HSP-110 has been previously identified in a genome-wide screen for proteostasis regulators in C. elegans , in which an organism-wide KD of HSP-110 reduced Q35 aggregation (Silva et al, 2011). In contrast, the same systemic KD resulted in increased Q35 aggregation in another study (Scior et al, 2018). The respective outcome is likely to depend on the timing and strength of the KD, and to what extent it affects the folding of proteins other than Q35, both in the same tissue and in neighboring tissues, which may also influence muscle cell proteostasis through non-autonomous mechanisms (Morimoto, 2019; Shai et al, 2014).…”

Section: Discussionmentioning

confidence: 90%

“…While previous work revealed that metazoan cells exhibit disaggregation activity and also contain all co-factors required for cytosolic propagation and dissemination of an ectopically expressed amyloid-like yeast prion (Cohen et al, 2006; Hofmann and Vorberg, 2013; Hofmann et al, 2013; Krammer et al, 2009a; Krammer et al, 2009b), the nature of these co-factor(s) was still unclear, since direct homologs of HPS104 are absent from the metazoan cytosol. The recent discovery of a metazoan disaggregation machinery in which a particular HSP110-type nucleotide exchange factor (NEF) cooperates with the human HSP70-DNAJ system to fragment and depolymerize amyloid aggregates (Gao et al, 2015; Scior et al, 2018) has raised the question of whether this activity could prevent or promote the prion-like propagation of amyloid-type aggregates in metazoans and what physiological implications this would have. Since prion-like amplification and intercellular spreading of disease-linked proteins is implicated in the propagation of the pathology in neurodegenerative diseases such as AD and PD, co-factors involved in this process might be potential therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

HSP110 dependent HSP70 disaggregation machinery mediates prion-like propagation of amyloidogenic proteins in metazoa

Tittelmeier

Sandhof

Ries

et al. 2019

Preprint

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The gradual accumulation and prion-like propagation of α -synuclein and other amyloidogenic proteins is associated with devastating neurodegenerative diseases. The metazoan disaggregation machinery, a specific combination of HSP70 and its co-chaperones, is able to disassemble α -synuclein fibrils in vitro, but the physiological consequence in vivo is unknown. To explore this, we used Caenorhabditis elegans models that exhibit pathological features of 6 RESULTS Tissue-specific KD of HSP-110 prevents disassembly of HS-induced firefly luciferase aggregatesOur previous work revealed that a specific human HSP70-DNAJ-HSP110 network exhibits in vitro disaggregation activity towards amyloid α -Syn fibrils and detergent insoluble α -Syn extracted from C. elegans (Gao et al., 2015). However, its effect on aggregation and toxicity of α -Syn in vivo has yet to be addressed. Two scenarios are conceivable. The disaggregation activity could either lead to a resolubilization and refolding of aggregated α -Syn, which would result in reduced toxicity. Alternatively, it could contribute to the multiplication ofα -Syn aggregates by continuously generating new seeds by fragmentation, analogous to the function of HSP104 and the HSP70-DNAJ system in yeast prion propagation, which would likely increase toxicity.In an effort to assess the role of the metazoan disaggregation machinery in amyloid aggregate propagation in vivo, we employed C. elegans as model organism. Members of the nematode disaggregation system are highly conserved, but less redundant than in the human system (Kirstein et al., 2017).

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Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex

Cited by 111 publications

References 49 publications

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

Functional Modules of the Proteostasis Network

HSP110 dependent HSP70 disaggregation machinery mediates prion-like propagation of amyloidogenic proteins in metazoa

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