Recent advances in α-synuclein functions, advanced glycation, and toxicity: implications for Parkinson's disease.

The toxicity of α-synuclein in the neuropathology of Parkinson's disease which includes its hallmark aggregation has been studied scrupulously in the last decade. Although little is known regarding the normal functions of α-synuclein, its association with membrane phospholipids suggests its potential role in signaling pathways. Following extensive evidences for its nuclear localization, we and others recently demonstrated DNA binding activity of α-synuclein that modulates its conformation as well as aggregation properties. Furthermore, we also underscored the similarities among various amyloidogenic proteins involved in neurodegenerative diseases including amyloid beta peptides and tau. Our more recent studies show that α-synuclein is glycated and glycosylated both in vitro and in neurons, significantly affecting its folding, oligomeric, and DNA binding properties. Glycated α-synuclein causes increased genome damage both via its direct interaction with DNA and by increased generation of reactive oxygen species as glycation byproduct. In this review, we discuss the mechanisms of glycation and other posttranslational modifications of α-synuclein, including phosphorylation and nitration, and their role in neuronal death in Parkinson's disease.

Comparison of single unit responses to tone, light, and compound conditioned stimuli during rabbit classical eyeblink conditioning.

Unit recordings and lesion studies have implicated the cerebellum as an essential site for the acquisition and maintenance of the conditioned eyeblink response. The current study looked at the neural characteristics of conditioned stimulus (CS) processing in the interpositus nucleus of the cerebellum after training New Zealand white rabbits (Oryctolagus cuniculus) in one of two conditioning paradigms: (a) compound conditioning (CMP), a compound CS consisting of light and tone paired with an air puff unconditioned stimulus (US); or (b) stimulus compounding (ALT), alternating blocks of tone CS and light CS trials paired with the air puff US. Single unit responses were recorded during five sessions after the animals had reached an asymptotic level of responding. Animals were tested for behavioral and neural responses to CS alone trials that included tone alone, light alone, and compound tone-light trials. For the CMP group, the compound CS elicited 80 to 90% conditioned eyeblink responses (CRs), whereas the individual tone and light CSs elicited only 40 to 50% CRs. For the ALT group, all three CSs (tone, light, and compound) elicited very high levels of responding of at least 80% CRs. For the CMP group, there were roughly equal numbers of cells responding to all of the CSs. This includes cells that responded exclusively to one, and only one, of the three stimuli and also those cells that responded to combinations of two or more. Cells from the ALT group were far more likely to respond exclusively to only one of the CSs. Both the behavioral and physiological results suggest that the compound tone-light stimulus was processed as a distinct stimulus, separate from the component tone and light. These results are discussed in the context of multisensory processing.

Learning-related interpositus activity is conserved across species as studied during eyeblink conditioning in the rat.

Single-unit activity was monitored in the interpositus nucleus of the cerebellum during standard delay conditioning of the eyeblink response in freely-moving rats. The rats were implanted with recording electrodes in the interpositus nucleus then received paired presentations of a tone-conditioned stimulus (CS) and eye-shock unconditioned stimulus during acquisition training. The acquisition training was followed by CS-alone extinction training. Learning-related activity in the interpositus nucleus developed over the course of acquisition training and then activity returned to baseline levels during subsequent extinction training. These findings are consistent with rabbit studies that have demonstrated similar changes in neuronal activity in the interpositus nucleus over the course of acquisition and extinction of the eyeblink response, thus providing strong evidence for the generality of the neural substrates of eyeblink conditioning across species.