Bioinorganic chemistry of copper coordination to alpha-synuclein: Relevance to Parkinson?s disease

BINOLFI, A; QUINTANAR, L; BERTONCINI, CW; GRIESINGER, C; FERNANDEZ, CO

COORDINATION CHEMISTRY REVIEWS

ELSEVIER SCIENCE SA

Lugar: Amsterdam; Año: 2012 p. 2188 - 2201

0010-8545

Alpha-synuclein (AS) aggregation is associated with neurodegeneration in Parkinson?s disease (PD). Atthe same time, alterations in metal ion homeostasis may play a pivotal role in the progression of ASamyloid assembly and the onset of PD. Elucidation of the structural basis directing AS?metal interactionsand their effect on AS aggregation constitutes a key step toward understanding the role of metal ionsin AS amyloid formation and neurodegeneration. This work provides a comprehensive review of recentadvances attained in the bioinorganic chemistry of AS amyloid diseases. A hierarchy in AS?metal ioninteractions has been established: while the physiologically relevant divalent metal ions iron andmanganese interact at a non-specific, low-affinity binding interface in the C-terminus of AS, copperbinds with high affinity at the N-terminal region and it is the most effective metal ion in accelerating ASfilament assembly. The strong link between metal binding specificity and its impact on aggregation isdiscussed here on a mechanistic basis. A detailed description of the structural features and coordinationenvironments of copper to AS is presented and discussed in the context of oxidative cellular events thatmight lead to the development of PD. Overall, the research observations presented here support thenotion that perturbations in copper metabolism may be a common upstream event in the pathogenesisof neurodegenerative processes.