Alpha Synuclein Oligomers in Human Pathology: Significance of Nitrative Alpha Synuclein Modifications
Martin, Zane 1975-
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Intracellular deposition of fibrillar β-sheet aggregates of αSyn is a pathological hallmark of synucleinopathies such as Parkinson disease (PD) and dementia with Lewy bodies (DLB), which are clinically characterized by motor and cognitive dysfunction. Recent evidence indicates that αSyn oligomer intermediates are the most neurotoxic species. However, the mechanism of action of αSyn oligomers remains elusive. Previous studies in our laboratory showed that αSyn oligomers cause increased intracellular calcium, thus promoting activation of protein phosphatase calcineurin and concomitant decrease in transcription factor pCREB, which disrupts synaptic integrity and memory. This phenomenon is observed in vitro, ex vivo, and in vivo and results in deficits in LTP, synaptic plasticity, and memory function. On this basis, I tested the hypothesis that similar effects on synaptic signaling can be observed in human brains from DLB patients. Here I report that in the brains of DLB patients there is an increase in activated calcineurin (CaN), a significant reduction of pCREB, and this is associated with the appearance of αSyn dimers. Furthermore, I determined the direct toxicity as well as the effect on αSyn oligomers of nitrated αSyn, an oxidative stress-related αSyn modification that has been reported to occur in human synucleopathies. My results show that, as compared to unmodified αSyn, nitrated αSyn elicits no increases in intracellular calcium, shorter LTP expression, and no effects on pCREB levels after sixty minute treatment but decreased cell viability after twenty-four hours. Notably, seeding of unmodified αSyn with small amounts of nitrated αSyn resulted in very stable oligomers that were substantially more toxic than non-seeded αSyn oligomers. Overall these results support the idea that increased CaN activity mediates some of the neuro-dysfunctional effects of aggregated αSyn in humans and may thus constitute a viable pharmacological target. These data also suggest that nitrative modifications of small amounts of αSyn, although not particularly toxic per se, may seed unmodified local αSyn to form stable oligomers that possess increased neurotoxicity. This observation may constitute a molecular mechanism linking oxidative/nitrative insult to synucein pathology that could trigger a detrimental cascade towards neurodegeneration.