Diverse Misfolded Conformational Strains and Cross-seeding of Misfolded Proteins Implicated in Neurodegenerative Diseases

Abstract

Numerous neurodegenerative diseases including prion, Alzheimer's and Parkinson's diseases are characterized by accumulation of protein aggregates in brain. Prion disease is unique in that the natively folded prion protein forms diverse misfolded aggregates with distinct molecular conformations (strains), which underlie different disease phenotypes. In addition, the conformational strains are able to self-propagate their unique conformations by recruiting normal protein monomers and converting their conformations to misfolded conformers. There is an increasing body of evidence that suggests other aggregation-prone proteins including tau and α-synuclein associated with Alzheimer's and Parkinson's diseases, respectively, also behave like a prion that has conformational strains with self-propagation (seeding) property. Moreover, misfolded protein aggregates can promote misfolding and aggregation of different proteins through cross-seeding, which might be associated with co-occurrence of multiple neurodegenerative diseases in the same patient. Elucidation of diverse conformational strains with self-propagation capability and of molecular basis for the cross-talk between misfolded proteins is essential to the development of effective therapeutic intervention.

Keywords: conformational strain; cross-seeding; misfolding; prion; tau; α-synuclein.

Figure 1

(A) Schematic diagram of aggregation process for an intrinsically disordered protein. Some of the aggregation-prone conformers in the conformational ensemble may form various oligomers that can self-assemble into fibrillar aggregates with different molecular conformations depending on different environments (Jahn and Radford, 2005). (B) Solid-state NMR structure of Aβ(1–42) filaments (sideview, left; top view, right). (C) Hydrogen bonding interactions between carbonyl carbon (red) and amide hydrogen (blue). (D) Salt bridges between NH3+ of K28 (blue) and COO⁻ of A42 (red) in Aβ(1–42) filaments. The filament structures were drawn with PDB accession number (5KK3).

Figure 2

(A) Solid-state NMR structure of α-synuclein filaments. (B–E) Cryo-EM structures of α-synuclein filaments. (F) Cryo-EM structures of tau filaments extracted from an AD patient. (G–J) Cryo-EM structures of tau filaments induced by heparin. (K) Cryo-EM structures of tau filaments extracted from a PiD patient. The filament structures were drawn with PDB accession numbers, 2N0A (A), 6A6B (B), 6FLT (C), 6CU7 (D), 6CU8 (E), 5O3L (F), 3QJM (G), 3QJP (H), 3QJH (I), 3QJQ (J), and 6GX5 (K).