SUMO and Alzheimer’s Disease

Abstract

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.

Tau-induced neurodegeneration: mechanisms and targets

“…SUMOylation is a post-translational modification process that regulates the functional properties of many proteins, among which several are implicated in neurodegenerative disease. Many proteins that have functions relevant to AD pathology have been identifi ed as SUMO substrates, including those involved in synaptic physiology, mitochondrial dynamics, and infl ammatory signaling [74] .Glycation of tau can occur via the non-enzymatic formation of advanced glycation end-products [75] . Tau can be glycated in vitro, resulting in a loss of microtubule binding.…”

SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

“…A number of studies alluded to the presence of SUMO1 in amyloid plaques (Lee et al., 2013). We therefore used our mouse model to test this notion.…”

“…The role of SUMOylation is particularly interesting in the context of neurodegenerative disorders with deregulated proteostasis (Feligioni et al., 2015; Krumova & Weishaupt, 2013; Lee, Sakurai, Matsuzaki, Arancio & Fraser, 2013; Liebelt & Vertegaal, 2016). Notably, SUMOylation can regulate the solubility of various disease‐associated proteins (Krumova & Weishaupt, 2013; Lee et al., 2013; Shahpasandzadeh et al., 2014).…”

“…Notably, SUMOylation can regulate the solubility of various disease‐associated proteins (Krumova & Weishaupt, 2013; Lee et al., 2013; Shahpasandzadeh et al., 2014). Furthermore, altered SUMOylation—at the global level of SUMOylated proteins or with regard to the SUMOylation status of specific disease‐related proteins—has been reported in the context of a large variety of neurological disorders with altered proteostasis, including AD as the most common age‐related neurological disorder (Lee et al., 2013; Martins, Tasca & Cimarosti, 2016). Indeed, several AD‐related proteins (such as α‐synuclein, tau, and APP) have been proposed to be SUMO1 conjugates (Martins et al., 2016).…”

SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?

“…In contrast to ubiquitin, which mainly tags proteins for degradation, SUMOylation is important for the normal functions of proteins in the cell. However, over the past few years, several studies have indicated that SUMOylation also has a role in aging and neurodegenerative diseases, including AD (Table 1) [32,33].…”