SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity

Hoppe, Juliana Bender; Rattray, Marcus; Tu, Henry; Salbego, Christianne Gazzana; Cimarosti, Helena

doi:10.1016/j.neulet.2013.04.050

Cited by 27 publications

(16 citation statements)

References 31 publications

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“…In AD, astrocytes undergo reactive gliosis which is accompanied by inflammatory signaling and morphological changes involving increases in glial fibrillary protein (GFAP). A recent study found that Aβ 42 exposure can decrease the levels of Ubc9 and SUMO1 conjugates in primary astrocyte cultures, concomitant with reactive astrogliosis (Hoppe et al 2013). Overexpression of SUMO1, but not a conjugation-deficient SUMO1, was found to prevent GFAP upregulation and morphological reactivity.…”

Section: Sumo and Glial Cellsmentioning

confidence: 99%

SUMO and Alzheimer’s Disease

et al. 2013

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and is the most common cause of dementia in the elderly. Histopathologically, AD features insoluble aggregates of two proteins in the brain, amyloid-β (Aβ) and the microtubule associated protein tau, both of which have been linked to the small ubiquitin-like modifier (SUMO). A large body of research has elucidated many of the molecular and cellular pathways that underlie AD, including those involving the abnormal Aβ and tau aggregates. However, a full understanding of the etiology and pathogenesis of the disease has remained elusive. Consequently, there are currently no effective therapeutic options that can modify the disease progression and slow or stop the decline of cognitive functioning. As part of the effort to address this lacking, there needs a better understanding of the signaling pathways that become impaired under AD pathology, including the regulatory mechanisms that normally control those networks. One such mechanism involves SUMOylation, which is a post-translational modification (PTM) that is involved in regulating many aspects of cell biology and has also been found to have several critical neuron-specific roles. Early studies have indicated that the SUMO system is likely altered with AD-type pathology, which may impact Aβ levels and tau aggregation. Although still a relatively unexplored topic, SUMOylation will likely emerge as a significant factor in AD pathogenesis in ways which may be somewhat analogous to other regulatory PTMs such as phosphorylation. Thus, in addition to the upstream effects on tau and Aβ processing, there may also be downstream effects mediated by Aβ aggregates or other AD-related factors on SUMO-regulated signaling pathways. Multiple proteins that have functions relevant to AD pathology have been identified as SUMO substrates, including those involved in synaptic physiology, mitochondrial dynamics and inflammatory signaling. Ongoing studies will determine how these SUMO-regulated functions in neurons and glial cells may be impacted by Aβ and AD pathology. Here, we present a review of the current literature on the involvement of SUMO in AD, as well as an overview of the SUMOylated proteins and pathways that are potentially dysregulated with AD pathogenesis.

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Section: Sumo and Glial Cellsmentioning

confidence: 99%

SUMO and Alzheimer’s Disease

et al. 2013

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“…Moreover, treatment with resveratrol (RSV), a polyphenolic compound acting as a pharmacological activator of SIRT1, is protective in a number of experimental neurodegeneration paradigms (Anekonda, 2006; Sun et al, 2010). Resveratrol, like other polyphenol compounds including curcumin, displays a plethora of actions, behaving as a potent antioxidant agent, increasing SUMOylation, and activating protein kinase C, all mechanisms able to counteract astrocyte reactivity and protect neurons (Jefremov et al, 2007; Hoppe et al, 2013; Menard et al, 2013). Finally, it has been observed that both SIRT1 overexpression and RSV treatment are able to significantly decrease the Aβ-induced activation of NF-κB, thus operating a simultaneous control on both neurodegeneration and neuroinflammation processes (Chen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimerâ€™s disease

Scuderi¹,

Stecca²,

Bronzuoli³

et al. 2014

Front. Pharmacol.

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Among neurodegenerative disorders, Alzheimer’s disease (AD) represents the most common cause of dementia in the elderly. Several genetic and environmental factors have been identified; however, aging represents the most important risk factor in the development of AD. To date, no effective treatments to prevent or slow this dementia are available. Sirtuins (SIRTs) are a family of NAD+-dependent enzymes, implicated in the control of a variety of biological processes that have the potential to modulate neurodegeneration. Here we tested the hypothesis that activation of SIRT1 or inhibition of SIRT2 would prevent reactive gliosis which is considered one of the most important hallmark of AD. Primary rat astrocytes were activated with beta amyloid 1-42 (Aβ 1-42) and treated with resveratrol (RSV) or AGK-2, a SIRT1 activator and a SIRT2-selective inhibitor, respectively. Results showed that both RSV and AGK-2 were able to reduce astrocyte activation as well as the production of pro-inflammatory mediators. These data disclose novel findings about the therapeutic potential of SIRT modulators, and suggest novel strategies for AD treatment.

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“…A more recent study implicated SUMO in the inflammatory signaling mediated by Aβ in primary astrocytes [48]. This study found that concomitant with astrogliosis, Aβ exposure down-regulates SUMO-1 conjugated proteins, as well as the conjugating enzyme, Ubc9, in astrocytes.…”

Section: Sumoylation and Neuroinflammationmentioning

confidence: 69%

“…SUMO-1 modulates Aβ generation via BACE1 accumulation. Hoppe et al, 2013 [48] SUMO-1 overexpression abrogates Aβ-induced increase in GFAP in primary astrocytes. Nisticò et al, 2013 [40] 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.…”

Section: Protein Sumoylationmentioning

confidence: 99%

SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?

2015

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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.

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SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity

Cited by 27 publications

References 31 publications

SUMO and Alzheimer’s Disease

SUMO and Alzheimer’s Disease

Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimerâ€™s disease

SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?

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