The role of SUMOylation in cerebral hypoxia and ischemia

Abstract

The process of protein modification by adding or detaching small ubiquitin-like modifiers (SUMO) proteins, called SUMOylation, contributes to the regulation of numerous processes in eukaryotic cells. SUMOylation also represents a key response and adaption mechanism to different forms of metabolic stress. The central nervous system (CNS) and neurons in particular are highly susceptible to hypoxic-ischemic stress due to the lack of significant oxygen and energy reserves. SUMOylation is observed in many molecular responses to metabolic stress in the brain, and is therefore supposed to represent an endogenous neuroprotective mechanism. However, the detailed roles of SUMOylation during CNS hypoxia-ischemia are not well understood so far. Moreover, SUMOylation is subjected to complex regulatory mechanisms and might exert protective, but also detrimental processes during hypoxic-ischemic stress. This review provides a comprehensive overview on SUMOylation processes under physiological and pathological conditions in the CNS. A particular spotlight is set on clinically relevant hypoxic-ischemic conditions such as stroke by focusing on peri- and postischemic SUMOylation in neurons and astrocytes. The review describes relevant SUMOylation targets in these cells to discuss confirmed and supposed downstream mechanisms potentially contributing to neuroprotection, but also to sometimes detrimental processes. The review further provides unique insights into the time course of SUMO responses during cerebral ischemia in different cerebral cell populations. This includes neurons, astrocytes, but also phagocytes that become activated (microglia) and/or migrate (macrophages/monocytes) to the ischemic CNS. Based on this compact knowledge, the review finally suggests potential directions for future basic and translational research.

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

“…Preventing the accumulation of Aβ in perivascular drainage pathways seems to be a valid therapeutic strategy in AD [16]. It has already been demonstrated that immunotherapy can remove established Aβ plaques from brain parenchyma by 90% [160,161], relieving the restricted diffusion of solutes through the extracellular spaces, ultimately leading to cognitive recovery [129,162]. However, this approach may increase presence of amyloid deposits within the vessel walls, promoting CAA and micro-bleeds [161].…”

SUMOylation in brain ischemia: Patterns, targets, and translational implications

“…This is due primarily to our limited understanding of the SUMO-modified proteome involved in brain ischemia. Many recent reviews have speculated on the potential effects on cerebral stroke/ ischemia outcomes of proteins known to be SUMO-targets in general 53,54 ; however, here we wish to focus only on those proteins that have been experimentally demonstrated to be SUMOylated in post-ischemic brains.…”

Quantitative high‐throughput screening identifies cytoprotective molecules that enhance SUMO conjugation via the inhibition of SUMO‐specific protease (SENP)2

“…For example, dynamin-related protein 1 SUMOylation suppresses cytochrome c release and protects the cell from apoptosis (34), whereas hypoxiainducible factor (HIF)-1a SUMOylation may promote HIF-1a degradation and thereby impair HIF-1a-mediated protective effects after ischemia (62). It must be noted that current knowledge with regard to specific SUMO targets involved in brain ischemia is highly limited, and the potential effects of individual SUMOylated proteins within complex pathologies such as brain ischemia are primarily speculative (63).…”