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

• Published in: International journal of molecular sciences Vol. 22; no. 23; p. 12983
• Main Authors: Franco, Aitor, Cuéllar, Jorge, Fernández-Higuero, José Ángel, de la Arada, Igor, Orozco, Natalia, Valpuesta, José M, Prado, Adelina, Muga, Arturo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.11.2021; MDPI
• Subjects: Aggregates; alpha-Synuclein - metabolism; Amyloid - metabolism; amyloid disassembly; Biocompatibility; Calpain; Calpain - pharmacology; chaperone; Chaperones; Clearances; Depolymerization; Dismantling; Fibrils; HSC70 Heat-Shock Proteins - metabolism; Hsc70 protein; HSP40 Heat-Shock Proteins - metabolism; Hsp70; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; human disaggregase; Humans; Intermediates; Molecular Chaperones - metabolism; N-Terminus; Pathogenesis; Post-translation; Protein Aggregates - physiology; Protein Aggregation, Pathological - pathology; Protein Processing, Post-Translational - physiology; Proteins; Proteolysis; Quality control; suprafibrillar assemblies; Synuclein; Synucleinopathies - pathology; Toxicity; α-synuclein; amyloid disassembly; Hsp70; chaperone; human disaggregase; suprafibrillar assemblies; Hsp40; α-synuclein
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312983

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.