Molecular targets underlying SUMO-mediated neuroprotection in brain ischemia

SUMOylation (small ubiquitin-like modifier conjugation) is an important post-translational modification which is becoming increasingly implicated in the altered protein dynamics associated with brain ischemia. The function of SUMOylation in cells undergoing ischemic stress and the identity of small ubiquitin-like modifier (SUMO) targets remain in most cases unknown. However, the emerging consensus is that SUMOylation of certain proteins might be part of an endogenous neuroprotective response. This review brings together the current understanding of the underlying mechanisms and downstream effects of SUMOylation in brain ischemia, including processes such as autophagy, mitophagy and oxidative stress. We focus on recent advances and controversies regarding key central nervous system proteins, including those associated with the nucleus, cytoplasm and plasma membrane, such as glucose transporters (GLUT1, GLUT4), excitatory amino acid transporter 2 glutamate transporters, K+ channels (K2P1, Kv1.5, Kv2.1), GluK2 kainate receptors, mGluR8 glutamate receptors and CB1 cannabinoid receptors, which are reported to be SUMO-modified. A discussion of the roles of these molecular targets for SUMOylation could play following an ischemic event, particularly with respect to their potential neuroprotective impact in brain ischemia, is proposed.

Increased protein SUMOylation following focal cerebral ischemia

Stroke is a major cause of death and disability, which involves excessive glutamate receptor activation leading to excitotoxic cell death. We recently reported that SUMOylation can regulate kainate receptor (KAR) function. Here we investigated changes in protein SUMOylation and levels of KAR and AMPA receptor subunits in two different animal stroke models: a rat model of focal ischemia with reperfusion and a mouse model without reperfusion. In rats, transient middle cerebral artery occlusion (MCAO) resulted in a striatal and cortical infarct. A dramatic increase in SUMOylation by both SUMO-1 and SUMO-2/3 was observed at 6h and 24h in the striatal infarct area and by SUMO-2/3 at 24h in the hippocampus, which was not directly subjected to ischemia. In mice, permanent MCAO resulted in a selective cortical infarct. No changes in SUMOylation occurred at 6h but there was increased SUMO-1 conjugation in the cortical infarct and non-ischemic hippocampus at 24h after MCAO. Interestingly, SUMOylation by SUMO-2/3 occurred only outside the infarct area. In both rat and mouse levels of KARs were only decreased in the infarct regions whereas AMPARs were decreased in the infarct and in other brain areas. These results suggest that posttranslational modification by SUMO and down-regulation of AMPARs and KARs may play important roles in the pathophysiological response to ischemia.

Ratings of age of acquisition of 299 words across 25 languages: is there a cross-linguistic order of words?

We present a new set of subjective age-of-acquisition (AoA) ratings for 299 words (158 nouns, 141 verbs) in 25 languages from five language families (Afro-Asiatic: Semitic languages; Altaic: one Turkic language: Indo-European: Baltic, Celtic, Germanic, Hellenic, Slavic, and Romance languages; Niger-Congo: one Bantu language; Uralic: Finnic and Ugric languages). Adult native speakers reported the age at which they had learned each word. We present a comparison of the AoA ratings across all languages by contrasting them in pairs. This comparison shows a consistency in the orders of ratings across the 25 languages. The data were then analyzed (1) to ascertain how the demographic characteristics of the participants influenced AoA estimations and (2) to assess differences caused by the exact form of the target question (when did you learn vs. when do children learn this word); (3) to compare the ratings obtained in our study to those of previous studies; and (4) to assess the validity of our study by comparison with quasi-objective AoA norms derived from the MacArthur–Bates Communicative Development Inventories (MB-CDI). All 299 words were judged as being acquired early (mostly before the age of 6 years). AoA ratings were associated with the raters’ social or language status, but not with the raters’ age or education. Parents reported words as being learned earlier, and bilinguals reported learning them later. Estimations of the age at which children learn the words revealed significantly lower ratings of AoA. Finally, comparisons with previous AoA and MB-CDI norms support the validity of the present estimations. Our AoA ratings are available for research or other purposes.

SUMOylation: novel neuroprotective approach for Alzheimer's disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized in the brain by the formation of amyloid-beta (Aβ)-containing plaques and neurofibrillary tangles containing the microtubule-associated protein tau. Neuroinflammation is another feature of AD and astrocytes are receiving increasing attention as key contributors. Although some progress has been made, the molecular mechanisms underlying the pathophysiology of AD remain unclear. Interestingly, some of the main proteins involved in AD, including amyloid precursor protein (APP) and tau, have recently been shown to be SUMOylated. The post-translational modification by SUMO (small ubiquitin-like modifier) has been shown to regulate APP and tau and may modulate other proteins implicated in AD. Here we present an overview of recent studies suggesting that protein SUMOylation might be involved in the underlying pathogenic mechanisms of AD and discuss how this could be exploited for therapeutic intervention.