The molecular path to Parkinson’s disease: amyloid aggregation of alpha-synuclein lit up by fluorescence.

CELEJ MS

La Plata, Argentina

Congreso; XXXVII Reunión Anual Soc. Arg. Biofisica; 2008

SAB

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Arial; mso-fareast-font-family:"Times New Roman";} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> Parkinson’s disease (PD) is a movement disorder characterized by the presence in the mid-brain of intracytoplasmatic inclusions (Lewy bodies), of which the main fibrillar constituent is the 140-aa protein a-synuclein (AS). AS is located presynaptically and functions in vesicle release and trafficking. Three missense point mutations (A53T, A30P and E46K) in the AS gene lead to early onset PD. The kinetics of AS aggregation is consistent with a nucleation-propagation mechanisms, starting from nucleation centers and progressing via oligomerization to an elongation phase leading to the formation of the characteristic fibrils. Cytotoxicity is currently attributed to the action of intermediate species rather than the end-state amyloid fibrils. These prefibrillar structures are generally not revealed by classical amyloid indicators. In a search for improved fluorescence tools for studying amyloid formation, the ability of N-arylaminonahthalene sulfonate derivatives to act as noncovalent probes of AS fibrillation will be presented [1].   The mature amyloid fibrils have an unbranched rod-like morphology and are formed by interwound protofilaments. The core structure is a stack of b-sheets, the strands of which are perpendicular to main axis of the fibril. Of particular interest is the ability of the b-sheet network within this canonical cross-b structure to adapt to point mutations. It is known that fibrils formed by AS familial mutants exhibit subtle differences in ultrastructural features as compared to the WT protein. It will be demonstrated that AS variants differ in their supramolecular fibrillar organization as sensed by a novel dual-emission color probe. These differences will be discussed in terms of distinctive polarity and hydration of the binding sites [2]. I am indebt to Dr T. Jovin (Lab. of Cellular Dynamics, MPIbpc, Germany), W. Caarls (Lab. of Cellular Dynamics, MPIbpc, Germany), E. Jares-Erijman (FCEyN, UBA, Argentina) and A. Demchenko (Palladin Institute, Ukraine) for their essential contributions to this work.