Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein

TLDR

Idiopathic Parkinson’s disease features Lewy bodies composed of aggregated α‑synuclein, yet the transition from its natively unfolded state to neurotoxic aggregates remains poorly understood. Paramagnetic relaxation enhancement and NMR dipolar coupling experiments revealed that monomeric α‑synuclein adopts long‑range interaction–stabilized conformations. These autoinhibitory conformations fluctuate on nanosecond‑to‑microsecond timescales, are disrupted by polyamine binding or heat to expose a fully unfolded state that aggregates readily, and suggest that stabilizing the native structure could reduce α‑synuclein oligomerization and aggregation in Parkinson’s disease.

Abstract

In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein α-synuclein (αS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, αS to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric αS assumes conformations that are stabilized by long-range interactions and act to inhibit oligomerization and aggregation. The autoinhibitory conformations fluctuate in the range of nanoseconds to micro-seconds corresponding to the time scale of secondary structure formation during folding. Polyamine binding and/or temperature increase, conditions that induce aggregation in vitro , release this inherent tertiary structure, leading to a completely unfolded conformation that associates readily. Stabilization of the native, autoinhibitory structure of αS constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.