Fibrillar α-synuclein (α-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of α-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with α-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of α-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble α-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble α-Syn, we set up experiments to identify the molecular chaperone-α-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and α-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-α-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p-derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α-Syn assembly and/or toxicity.
Fibrillar α - synuclein ( α - Syn ) is the principal component of Lewy bodies , which are evident in individuals affected by Parkinson disease ( PD ) . This neuropathologic form of α - Syn plays a central role in PD progression as it has been shown to propagate between neurons . Tools that interfere with α - Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell - to - cell transmission and the systematic spread of α - Syn assemblies within the central nervous system . Vertebrate molecular chaperones from the constitutive / heat - inducible heat shock protein 70 ( Hsc / p70 ) family have been shown to hinder the assembly of soluble α - Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity . To understand how Hsc70 family members sequester soluble α - Syn , we set up experiments to identify the molecular chaperone - α - Syn surface interfaces . We cross - linked human Hsc70 and its yeast homologue Ssa1p and α - Syn using a chemical cross - linker and mapped the Hsc70- and Ssa1p - α - Syn interface . We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α - Syn similar to a tweezer , with the first spanning residues 10 - 45 and the second spanning residues 97 - 102 . Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p - derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α - Syn assembly and/or toxicity .
Which is the primary protein component of Lewy bodies?
Which is the primary protein component of Lewy bodies ?
α-synuclein
alpha-synuclein α-synuclein αSyn