Early-Onset Parkinson Mutation Remodels Monomer–Fibril Interactions to Allosterically Amplify Synuclein’s Amyloid Cascade

Abstract

Alpha synuclein (αS) aggregates are the main component of Lewy bodies (LBs) associated with Parkinson’s disease (PD). A longstanding question about αS and PD pertains to the autosomal dominant E46K αS mutant, which leads to the early onset of PD and LB dementias. The E46K mutation not only promotes αS aggregation but also stabilizes αS monomers in “closed” conformers, which are compact and aggregation-incompetent. Hence, the mechanism of action of the E46K mutation is currently unclear. Here, we show that αS monomers harboring the E46K mutation exhibit more extensive interactions with fibrils compared to those of WT. Such monomer-fibril interactions are sufficient to allosterically drive transitions of αS monomers from closed to open conformations, enabling αS aggregation. We also show that E46K promotes head-to-tail monomer–monomer interactions in early self-association events. This multipronged mechanism provides a new framework to explain how the E46K mutation and possibly other αS variants trigger early-onset PD.

α-Synuclein and Mitochondria: Probing the Dynamics of Disordered Membrane-protein Regions Using Solid-State Nuclear Magnetic Resonance

“…Recent advances have also enabled the quantification of biomolecular dynamics via CP ssNMR, still in the context of rigid and homogeneous protein states. To quantitatively probe the dynamical content of IDRs of proteins at the surface of biological lipid bilayers, we here measured 15 N relaxation through insensitive nuclei enhanced by polarization transfer (INEPT) MAS measurements. , This method of transferring nuclear spin polarization is largely employed in solution-state NMR and has also been applied in combination with MAS ssNMR to selectively probe the resonances of highly dynamical regions of biomolecules. − We used INEPT-based MAS ssNMR to quantitatively study the dynamics of the membrane-bound state of α-synuclein (αS), a 14 kDa protein that localizes predominantly at the presynaptic terminals of neurons and whose aberrant aggregation is associated with Parkinson’s disease (PD). ,− We focused on the binding of αS with mitochondria, as evidence exists for the localization of αS on mitochondrial membranes (outer, inner, , and both types of membranes) , as well as to mitochondrial-associated membranes . There is large interest in characterizing this interaction owing to the relevance of mitochondrial dysfunction in the pathogenesis of PD and other neurodegenerative disorders. − Evidences also indicate that αS induces mitochondrial fragmentation ,, particularly when in the form of the PD variant A53T .…”