SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?
Juliana B. Hoppe1, Christianne G. Salbego1, Helena Cimarosti2,*()
1 Laboratory of Neuroprotection and Cell Signaling, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil 2 Reading School of Pharmacy, University of Reading, Reading, RG6 6UB, UK
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. Neuroin?ammation 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.
Figure 1. The SUMO conjugation pathway. SUMO is expressed as a precursor protein and processed by a SUMO protease (SENP). Mature SUMO is activated in an ATP-dependent manner by the SUMO activating enzyme (E1) and is transferred through a transesterification process to the unique SUMO conjugating enzyme (E2) Ubc9. SUMO is next conjugated to the target lysine of a substrate (consensus sequence ΨKXE/D). Conjugation, in some instances, is facilitated by a SUMO E3 ligase. The sumoylation pathway is reversible as specific proteases can remove and recycle SUMO from modified substrates.
Study (author and year)
Li et al., 2003 
SUMO-3 overexpression reduces Aβ production via regulation of APP processing in HEK293 cells. Monosumoylation has a positive effect on Aβ production as opposed to polysumoylation, which negatively regulates Aβ production.
Dorval and Fraser, 2006 
Inhibition of phosphatases by okadaic acid increased SUMO1-tau levels in HEK293 cells.
Dorval et al., 2007 
SUMO-3 overexpression increases Aβ40/Aβ42 secretion and up-regulates the expression of BACE. Suppression of SUMO-1 or SUMO-2 does not affect APP levels or Aβ production in HEK293 cells.
Takahashi et al., 2008 
SUMO-1 and phospho-tau colocalization is observed in degenerating neurites around neuritic amyloid plaques in the cortex of aged mice.
Zhang and Sarge, 2008 
Sumoylation of lysines 587 and 595 of APP is associated with decreased levels of Aβ aggregates in HeLa cells.
Ahn et al., 2009 
Genetic variations of Ubc9 gene might be associated with a risk of AD in the Korean population.
Akar and Feinstein, 2009 
LPS decreases mRNA levels of SUMO-1, Ubc9 and SENP1 in primary astrocytes and a similar decrease occurred during normal aging in brain.
Lee et al., 2009 
SUMOylation is required for the suppression of STAT1-dependent inflammatory responses by LXRs in IFN-γ-stimulated brain astrocytes.
McMillan et al., 2011 
Changes in individual bands of SUMO-1 or SUMO-2/3 conjugation are apparent in the hippocampus, cortex and cerebellum, although global levels were unaltered in Tg2576 mice (9 months).
Fang et al., 2011 
BACE gene promoter activity is inhibited by the overexpression of SUMO proteins.
Yang et al., 2012 
Free unconjugated SUMO-3 increases in the hippocampus may be correlated with spatial learning ability in old C57BL/6 mice.
Yun et al., 2013 
SUMO-1 free protein is elevated compared to wild-type mice in APP/ PS1 double transgenic mice. SUMO-1 modulates Aβ generation via BACE1 accumulation.
Hoppe et al., 2013 
SUMO-1 overexpression abrogates Aβ-induced increase in GFAP in primary astrocytes.
Nisticò et al., 2013 
SUMO-1 conjugation is increased in Tg2576 mice in cortex and hippocampus (3 and 6 months) and this is paralleled by increased expression levels of Ubc9 and SENP1 in both brain regions. SUMO-2-ylation is decreased in old transgenic mice (17 months), concomitant with an elevated amyloid deposition, which occurs at this stage in AD mice model.
Table 1 The involvement of SUMOylation in Alzheimer’s disease, aging and neuroinflammation.
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