We tune the coordination environment of macrocyclic ligands to design two novel fluorescence sensors for Mn(2+). The BODIPY-based Mn(2+) sensor M1 affords an excellent, 52 fold, fluorescence 'turn-on' response despite the paramagnetic nature of Mn(2+). The lipophilic probe is cell-permeable and confocal imaging demonstrates that the sensor distinctly detects Mn(2+) within live cells.

We report highly selective, novel Cu2+ chelators that relieve copper induced oxidative stress in vivo indicating applicability toward assuaging copper-overload disorders.

O-GlcNAc modification of the microtubule associated protein tau and α-synuclein can directly inhibit the formation of the associated amyloid fibers associated with major classes of neurodegenerative diseases. However, the mechanism(s) by which this posttranslational modification (PTM) inhibit amyloid aggregation are still murky. One hypothesis is that O-GlcNAc simply acts as a polyhydroxylated steric impediment to the formation of amyloid oligomers and fibers. Here, we begin to test this hypothesis by comparing the effects of O-GlcNAc to other similar monosaccharidesglucose, N-acetyl-galactosamine (GalNAc), or mannoseon α-synuclein amyloid formation. Interestingly, we find that this quite reasonable hypothesis is not entirely correct. More specifically, we used four types of biochemical and biophysical assays to discover that the different sugars display different effects on the inhibition of amyloid formation, despite only small differences between the structures of the monosaccharides. These results further support a more detailed investigation into the mechanism of amyloid inhibition by O-GlcNAc and has potential implications for the evolution of N-acetyl-glucosamine as the monosaccharide of choice for widespread intracellular glycosylation.

Toxic amyloid aggregates are a feature of many neurodegenerative diseases. A number of biochemical and structural studies have demonstrated that not all amyloids of a given protein are equivalent but rather that an aggregating protein can form different amyloid structures or polymorphisms. Different polymorphisms can also induce different amounts of pathology and toxicity in cells and in mice, suggesting that the structural differences may play important roles in disease. However, the features that cause the formation of polymorphisms in vivo are still being uncovered. Posttranslational modifications on several amyloid forming proteins, including the Parkinson’s disease causing protein α-synuclein, may be one such cause. Here, we explore whether ubiquitination can induce structural changes in α-synuclein aggregates in vitro. We used protein chemistry to first synthesize ubiquitinated analogues at three different positions using disulfide linkages. After aggregation, these linkages can be reversed, allowing us to make relative comparisons between the structures using a proteinase K assay. We find that, while ubiquitination at residue 6, 23, or 96 inhibits α-synuclein aggregation, only modification at residue 96 causes an alteration in the aggregate structure, providing further evidence that posttranslational modifications may be an important feature in amyloid polymorphism formation.