Molecular chaperones in the assembly of α-Synuclein and Parkinson’s Disease
type: Dataset
description: The formation and deposition of α-Synuclein fibrils in the human brain is at the origin of Parkinson’s disease. The objective of my thesis was to document the role of two molecular chaperones on the assembly of α-Syn into fibrils: Hsc70, a constitutively expressed human heat shock protein, and Ssa1p, its yeast equivalent. The aim was to expand the catalogue of known effects of molecular chaperones on the PD implicated protein, which could have therapeutic significance. We showed that Hsc70 inhibits the assembly of α-Syn into fibrils, by binding with high affinity to the soluble form of α-Syn. We documented that Hsc70 binds preferentially to α-Syn fibrils and that this binding has a cytoprotective effect, as it renders the fibrils less toxic to cultured mammalian cells. Similarly to Hsc70, Ssa1p inhibits the assembly of α-Syn into fibrils, and has a higher affinity for fibrils than for the soluble form of α-Syn. On the other hand, binding of Ssa1p to α-Syn fibrils does not have a cytoprotective effect, almost certainly due to differences in the amino acid sequences of the peptide binding sites of the two molecular chaperones, which mean that Ssa1p has a lower affinity than Hsc70 for α-Syn fibrils. We stabilized the complex between Ssa1p and α-Syn using chemical cross-linkers, to then map the interaction site between the two proteins. This is indispensable if a “mini” Ssa1p, comprised of only what is necessary and sufficient of Ssa1p, is to be used as a therapeutic agent to decrease the toxicity of α-Syn fibrils. A therapeutic agent based on exogenous protein Ssa1p is less likely to trigger an autoimmune response than for example the endogenous protein Hsc70.
landing page: https://theses.hal.science/tel-00762970
identifier: NNT: 2011PA114840
keyword: co-chaperones
keyword: co-chaperons
keyword: fibrils
keyword: heat-shock-protein
keyword: hsc70
keyword: infoeu-reposemanticsdoctoralthesis
keyword: lpha-synuclein
keyword: lpha-synucleine
keyword: molecular-chaperones
keyword: oligomers
keyword: parkinsons-disease
keyword: protein-assembly
keyword: protein-folding
keyword: sdvmheplife-sciences-q-biohuman-health-and-pathology
keyword: sdvsalife-sciences-q-bioagricultural-sciences
keyword: ssa1p
keyword: theses
issued: 2026-06-01T04:41:59.107506
modified: 2026-06-01T04:41:59.107514
language: en
contact point: Organization
  fn: CCSD

test_moissonnage_selune
type: Agent

Molecular chaperones in the assembly of α-Synuclein and Parkinson’s Disease
type: Distribution
format: HTML
access URL: https://theses.hal.science/tel-00762970
issued: 2026-06-01T04:41:59.265946
modified: 2026-06-01T04:41:59.043474