Divisional Seminar | Switching on Endogenous Metal Binding Proteins in Parkinson’s Disease

The formation of cytotoxic intracellular protein aggregates is a pathological signature of multiple neurodegenerative diseases. The principle aggregating protein in Parkinson’s disease (PD) and atypical Parkinson’s diseases is alpha-synuclein (a-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger a-syn aggregation, including raised calcium, iron, and copper. We have investigated transcriptional inducers to upregulate expression of endogenous metal-binding proteins as a potential neuroprotective strategy. The vitamin-D analogue, calcipotriol, induced increased expression of the neuronal vitamin D-dependent calcium-binding protein, calbindin-D28k, and this significantly decreased the occurrence of a-syn aggregates in cells with transiently raised intracellular free calcium, thereby increasing viability. More recently, the induction of endogenous expression of the zinc and copper binding protein, metallothionein, by the glucocorticoid analogue, dexamethasone, gave a specific reduction in copper-dependent a-syn aggregates. Our work suggests that transcriptional inducers may have potential as novel mechanism-based drugs against metal overload in PD.