SUMOylation and calcium signalling: potential roles in the brain and beyond

Small ubiquitin-like modi er (SUMO) conjugation (or SUMOylation) is a post-translational protein modi cation implicated in alterations to protein expression, localization and func- tion. Despite a number of nuclear roles for SUMO being well characterized, this process has only started to be explored in relation to membrane proteins, such as ion channels. Cal- cium ion (Ca2+) signalling is crucial for the normal functioning of cells and is also involved in the pathophysiological mechanisms underlying relevant neurological and cardiovascu- lar diseases. Intracellular Ca2+ levels are tightly regulated; at rest, most Ca2+ is retained in organelles, such as the sarcoplasmic reticulum, or in the extracellular space, whereas depolarization triggers a series of events leading to Ca2+ entry, followed by extrusion and reuptake. The mechanisms that maintain Ca2+ homoeostasis are candidates for modulation at the post-translational level. Here, we review the effects of protein SUMOylation, including Ca2+ channels, their proteome and other proteins associated with Ca2+ signalling, on vital cellular functions, such as neurotransmission within the central nervous system (CNS) and in additional systems, most prominently here, in the cardiac system

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 α-synuclein (α-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger α-syn aggregation, including raised calcium, iron, and copper. Transcriptional inducers have been explored 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 α-syn aggregates in cells with transiently raised intracellular free Ca, thereby increasing viability. More recently, the induction of endogenous expression of the Zn and Cu binding protein, metallothionein, by the glucocorticoid analogue, dexamethasone, gave a specific reduction in Cu-dependent α-syn aggregates. Fe accumulation has long been associated with PD. Intracellularly, Fe is regulated by interactions between the Fe storage protein ferritin and Fe transporters, such as poly(C)-binding protein 1. Analysis of the transcriptional regulation of Fe binding proteins may reveal potential inducers that could modulate Fe homoeostasis in disease. The current review highlights recent studies that suggest that transcriptional inducers may have potential as novel mechanism-based drugs against metal overload in PD