Bcl-2-Homology-Only Proapoptotic Peptides Modulate ß-Amyloid Aggregation and Toxicity.

Aggregation of the ß-Amyloid (Aß) peptide in brain tissues is the hallmark of Alzheimer's disease (AD). While Aß is presumed to be insidiously involved in the disease's pathophysiology, concrete mechanisms accounting for the role of Aß in AD are yet to be deciphered. While Aß has been primarily identified in the extracellular space, the peptide also accumulates in cellular compartments such as mitochondria and lysosomes and impairs cellular functions. Here, we show that prominent proapoptotic peptides associated with the mitochondrial outer membrane, the Bcl-2-homology-only peptides BID, PUMA, and NOXA, exert significant and divergent effects upon aggregation, cytotoxicity, and membrane interactions of Aß42, the main Aß homolog. Interestingly, we show that BID and PUMA accelerated aggregation of Aß42, reduced Aß42-induced toxicity and mitochondrial disfunction, and inhibited Aß42-membrane interactions. In contrast, NOXA exhibited opposite effects, reducing Aß42 fibril formation, affecting more pronounced apoptotic effects and mitochondrial disfunction, and enhancing membrane interactions of Aß42. The effects of BID, PUMA, and NOXA upon the Aß42 structure and toxicity may be linked to its biological properties and affect pathophysiological features of AD.

Fibrils of α-Synuclein Abolish the Affinity of Cu2+-Binding Site to His50 and Induce Hopping of Cu2+ Ions in the Termini.

The effect of Cu2+ on α-synuclein (AS) aggregation is important because clinical studies of patients with Parkinson's disease have shown elevated levels of Cu2+ in the cerebrospinal fluid. So far, the molecular architectures of Cu2+-AS fibril complexes at atomic resolution are unknown. The current work identifies for the first time that His50 cannot bind Cu2+ ions in mature fibrils. Moreover, it shows hopping of Cu2+ ions between residues in AS fibrils and changes in the Cu2+ coordination mode in Cu2+ ions that bind in the termini of AS. The current study combines extensive experimental techniques, density functional theory calculations, and computational modeling tools to provide a complete description of the Cu2+ binding site in AS fibrils. Our findings illustrate for the first time the specific interactions between Cu2+ ions and AS fibrils, suggesting a new mechanistic perspective on the effect of Cu2+ ions on AS aggregation.