SUMOtherapeutics for Ischemic Stroke

Abstract

The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.

Keywords: SUMOylation; experimental therapeutics; ischemia; neuroprotection; stroke.

Figure 1

SUMOylation in cerebral ischemia. A pool of unconjugated SUMO is kept in reserve during normoxic conditions. After vascular occlusion, (1) the lack of perfusion results in an ischemic insult. When stressors are detected within the microenvironment, the conjugation of the SUMO reserve is rapidly upregulated. SUMOylation (2) is a process analogous to that of ubiquitination. The process of SUMOylation and de-SUMOylation is highly dynamic and the subject of significant regulatory interplay. Endogenous deSUMOylators, such as SENP2 and miRNA-182/183, thus represent therapeutic targets. SUMOylated target proteins have a variety of fates (3) that may impact their functionality, conformation, or location within the cellular milieu. Ultimately, SUMOylated proteins affect a variety of (4) pro-survival and pro-regeneration changes, including managing the response to ischemia, managing ion homeostasis, and encouraging the survival of endogenous/exogenous neural stem cell (NSC) populations. To this end, the regenerative nature of the SUMO response to ischemia stands in stark contrast against the apoptotic and degenerative response that is prevalent within the ischemic brain.