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Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase

1
Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain
2
Instituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, 48940 Leioa, Spain
3
Department of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain
4
Fundación Biofísica Bizkaia/Biofisika Bizkaia Fundazioa (FBB), Barrio Sarriena s/n, 48940 Leioa, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(23), 12983; https://doi.org/10.3390/ijms222312983
Received: 19 November 2021 / Revised: 28 November 2021 / Accepted: 28 November 2021 / Published: 30 November 2021
(This article belongs to the Section Biochemistry)
The aggregation of α-synuclein is the hallmark of a collective of neurodegenerative disorders known as synucleinopathies. The tendency to aggregate of this protein, the toxicity of its aggregation intermediates and the ability of the cellular protein quality control system to clear these intermediates seems to be regulated, among other factors, by post-translational modifications (PTMs). Among these modifications, we consider herein proteolysis at both the N- and C-terminal regions of α-synuclein as a factor that could modulate disassembly of toxic amyloids by the human disaggregase, a combination of the chaperones Hsc70, DnaJB1 and Apg2. We find that, in contrast to aggregates of the protein lacking the N-terminus, which can be solubilized as efficiently as those of the WT protein, the deletion of the C-terminal domain, either in a recombinant context or as a consequence of calpain treatment, impaired Hsc70-mediated amyloid disassembly. Progressive removal of the negative charges at the C-terminal region induces lateral association of fibrils and type B* oligomers, precluding chaperone action. We propose that truncation-driven aggregate clumping impairs the mechanical action of chaperones, which includes fast protofilament unzipping coupled to depolymerization. Inhibition of the chaperone-mediated clearance of C-truncated species could explain their exacerbated toxicity and higher propensity to deposit found in vivo. View Full-Text
Keywords: α-synuclein; amyloid disassembly; suprafibrillar assemblies; chaperone; human disaggregase; Hsp70; Hsp40 α-synuclein; amyloid disassembly; suprafibrillar assemblies; chaperone; human disaggregase; Hsp70; Hsp40
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MDPI and ACS Style

Franco, A.; Cuéllar, J.; Fernández-Higuero, J.Á.; de la Arada, I.; Orozco, N.; Valpuesta, J.M.; Prado, A.; Muga, A. Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase. Int. J. Mol. Sci. 2021, 22, 12983. https://doi.org/10.3390/ijms222312983

AMA Style

Franco A, Cuéllar J, Fernández-Higuero JÁ, de la Arada I, Orozco N, Valpuesta JM, Prado A, Muga A. Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase. International Journal of Molecular Sciences. 2021; 22(23):12983. https://doi.org/10.3390/ijms222312983

Chicago/Turabian Style

Franco, Aitor, Jorge Cuéllar, José Á. Fernández-Higuero, Igor de la Arada, Natalia Orozco, José M. Valpuesta, Adelina Prado, and Arturo Muga. 2021. "Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase" International Journal of Molecular Sciences 22, no. 23: 12983. https://doi.org/10.3390/ijms222312983

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