SUMO-1 modification increases human SOD1 stability and aggregation

Fei, Erkang; Jia, Nali; Yan, Ming; Ying, Zheng; Sun, Qibin; Wang, Hongfeng; Zhang, Tao; Ma, Xiaochuan; Ding, Husheng; Yao, Xuebiao; Shi, Yunyu; Wang, Guanghui

doi:10.1016/j.bbrc.2006.06.092

Cited by 84 publications

(57 citation statements)

References 41 publications

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“…The involvement of SUMO modification in the formation of SOD1 mutant -positive aggregates observed in ALS has already been evaluated in nonneuronal CHO and HEK293 cells expressing high concentrations of SUMO proteins and of the UBE2I SUMO-conjugating enzyme [13,14]. Here we report for the first time that the expression of several mutated forms of SOD1 in the NSC-34 motor neuronal cells induces the formation of cytosolic and sometimes nuclear aggregates containing the SUMO-1 protein.…”

Section: Discussionmentioning

confidence: 72%

“…Data in CHO and HEK293 cells suggested that SUMOylation may influence the aggregation of mutant SOD1 [13,14]. We wondered whether SUMO modification of SOD1 mutants was also involved in aggregate formation in motor neuronal cells.…”

Section: Resultsmentioning

confidence: 99%

“…The lysine 75 of the predicted SUMOylation PKDE site localized at the external surface of SOD1 was shown to be SUMOylated in HEK293 cells [13] (fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

“…In vitro studies have indicated that the overexpression of SUMO-1 or SUMO-3 in cells resulted in SUMO modifications of wild-type or mutant human SOD1, increasing SOD1-positive aggregates [13,14]. These studies on aggregate formation were performed in the human embryonic kidney cell line HEK293 and in the Chinese hamster ovary cell line CHO.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75

Dangoumau

Marouillat

Gaillard³

et al. 2015

Neurodegener Dis

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons. Mutations in the SOD1 gene encoding the superoxide dismutase 1 are present in 15% of familial ALS cases and in 2% of sporadic cases. These mutations are associated with the formation of SOD1-positive aggregates. The mechanisms of aggregation remain unknown, but posttranslational modifications of SOD1 may be involved. Here, we report that NSC-34 motor neuronal cells expressing mutant SOD1 contained aggregates positive for small ubiquitin modifier-1 (SUMO-1), and in parallel a reduced level of free SUMO-1. CLEM (correlative light and electron microscopy) analysis showed nonorganized cytosolic aggregates for all mutations tested (SOD1^A4V, SOD1^V31A, and SOD1^G93C). We next show that preventing the SUMOylation of mutant SOD1 by the substitution of lysine 75, the SUMOylation site of SOD1, significantly reduces the number of motor neuronal cells with aggregates. These results support the need for further research on the SUMOylation pathways, which may be a potential therapeutic target in ALS.

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

“…The lysine 75 of the predicted SUMOylation PKDE site localized at the external surface of SOD1 was shown to be SUMOylated in HEK293 cells [13] (fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75

Dangoumau

Marouillat

Gaillard³

et al. 2015

Neurodegener Dis

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“…A SUMOdependent increase in high-molecular weight species was observed for mutant superoxide dismutase 1 (SOD1), which is the cause of a familial form of ALS. 8 Principally in contrast to the study by Krumova et al, a higher proportion of oligomeric α-synuclein species was seen upon SUMO protein modification in vitro but only upon proteasome inhibition. 9 As SUMO attachments obviously play an important role in aggregate formation of neurodegeneration-related proteins, SUMO site-deficient mutants represent also versatile tools to study the effects of respective targeted manipulation of protein aggregation properties.…”

mentioning

confidence: 63%

Sumoylation fights “aggregopathies”

Krumova¹,

Weishaupt²

2012

Cell Cycle

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Sumoylation of the astroglial glutamate transporter EAAT2 governs its intracellular compartmentalization

Foran

Rosenblum

Bogush

et al. 2014

Glia

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EAAT2 is a predominantly astroglial glutamate transporter responsible for the majority of synaptic glutamate clearance in the mammalian CNS. Its dysfunction has been linked to many neurological disorders, including amyotrophic lateral sclerosis (ALS). Decreases in EAAT2 expression and function have been implicated in causing motor neuron excitotoxic death in ALS. Nevertheless, increasing EAAT2 expression does not significantly improve ALS phenotype in mouse models or in clinical trials. In the SOD1-G93A mouse model of inherited ALS, the cytosolic carboxy-terminal domain is cleaved from EAAT2, conjugated to SUMO1, and accumulated in astrocytes where it triggers astrocyte-mediated neurotoxic effects as disease progresses. However, it is not known whether this fragment is sumoylated after cleavage or if full-length EAAT2 is already sumoylated prior to cleavage as part of physiological regulation. In this study, we show that a fraction of full-length EAAT2 is constitutively sumoylated in primary cultures of astrocytes in vitro and in the CNS in vivo. Furthermore, the extent of sumoylation of EAAT2 does not change during the course of ALS in the SOD1-G93A mouse and is not affected by the expression of ALS-causative mutant SOD1 proteins in astrocytes in vitro, indicating that EAAT2 sumoylation is not driven by pathogenic mechanisms. Most interestingly, sumoylated EAAT2 localizes to intracellular compartments, while non-sumoylated EAAT2 resides on the plasma membrane. In agreement, promoting desumoylation in primary astrocytes causes increased EAAT2–mediated glutamate uptake. These findings could have implications for optimizing therapeutic approaches aimed at increasing EAAT2 activity in the dysfunctional or diseased CNS.

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SUMO-1 modification increases human SOD1 stability and aggregation

Cited by 84 publications

References 41 publications

Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75

Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75

Sumoylation fights “aggregopathies”

Sumoylation of the astroglial glutamate transporter EAAT2 governs its intracellular compartmentalization

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