Task: Question Generation
Input (English): Fibrillar -synuclein (-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of -Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with -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 -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 -Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble -Syn, we set up experiments to identify the molecular chaperone--Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and -Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p--Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within -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 -Syn assembly and/or toxicity.
Output (English): Which is the primary protein component of Lewy bodies?