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

BERTONCINI CW, JUNG YS, FERNÁNDEZ CO, HOYER W, GRIESINGER C, JOVIN TM, ZWECKSTETTER M.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Año: 2005 vol. 102 p. 1430 - 1435

0027-8424

In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) of the protein alpha-synuclein are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded,  alpha-synuclein to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric alpha-synuclein 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 microseconds 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 alpha-synuclein constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.