SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy

Pountney, Dean L.; Chegini, Fariba; Shen, Xiaofeng; Blumbergs, Peter; Gai, Wei-Ping

doi:10.1016/j.neulet.2005.02.013

Cited by 58 publications

(36 citation statements)

References 32 publications

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“…However, more recent investigations have demonstrated co-localization of ␣-synuclein deposits with SUMO1 (39). Our observation of specific ␣-synuclein sumoylation further supports the observation of SUMO immunoreactivity in the characteristic inclusions found in Parkinson disease and multiple system atrophy (39).…”

Section: Discussionsupporting

confidence: 88%

“…Sumoylation plays an important role in many cellular processes. Recent reports have also implicated sumoylation in neurodegeneration (35)(36)(37)(38)(39), and many proteins involved in these pathologies were found to be SUMO targets (40 -42). We therefore evaluated whether the two brain proteins, tau and ␣-synuclein, were sumoylated.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, one can speculate that sumoylation may prevent tau turnover via both mechanisms, through the inhibition of ubiquitination or prevention of its translocation into the proteasome catalytic chamber. Interestingly, sumoylation has recently been implicated in the pathogenesis of several neurodegenerative diseases that may, for example, be linked to proteasome dysfunction (35)(36)(37)(38)(39). Recent reports have revealed that a growing number of proteins involved in neurodegeneration, such as ataxin-1 (40), Huntingtin (41), DJ-1 (42), and tau and ␣-synuclein (current work), are sumoylated, which represents an as yet unexplored pathway in terms of their function, cellular regulation, and potential involvement in the disease process.…”

Section: Discussionmentioning

confidence: 99%

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Small Ubiquitin-like Modifier (SUMO) Modification of Natively Unfolded Proteins Tau and α-Synuclein

Dorval

Fraser

2006

Journal of Biological Chemistry

263

281

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Sumoylation is an important post-translational modification that provides a rapid and reversible means for controlling the activity, subcellular localization, and stability of target proteins. We have examined the covalent attachment of the small ubiquitin-like modifier (SUMO) proteins to tau and ␣-synuclein, two natively unfolded proteins that define several neurodegenerative diseases. Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences, and mutational analyses identified Lys 340 as the major sumoylation site. Although both tau and ␣-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Tau is a microtubule-associated protein, whose ability to bind and stabilize microtubules is negatively regulated by phosphorylation. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation. This suggests that SUMO modification may preferentially target a free soluble pool of the substrate. These findings revealed a new, possibly regulatory, modification of tau and ␣-synuclein that may also have implications for their pathogenic roles in neurodegenerative diseases. Small ubiquitin-like modifier proteins (SUMO)2 display similarities to ubiquitin in both the structure and the biochemistry of their conjugation (for review, see Ref. 1). SUMO isoforms are expressed in humans and display cell type-specific expression levels and distinct, although not exclusive, subcellular localizations (2). Each SUMO paralog is expressed as a precursor protein that undergoes processing by a C-terminal hydrolase (3). Once cleaved, the mature protein has a diglycine motif exposed at the C terminus and is ready to enter a multistep enzymatic pathway, which is similar but quite distinct from ubiquitination. Mature SUMO proteins are primed in an ATP-dependent manner by the SUMO-activating (E1) enzyme Sua1/hUba2 (4, 5). Activated SUMO is then transferred, through a trans-esterification reaction, to a unique conjugating (E2) enzyme, Ubch9 (6, 7). The final step is the formation of an isopeptide bond between the C-terminal glycine of SUMO and the lysine ⑀-amino group of the target substrate. A majority of the acceptor lysine residues are found within a SUMO consensus motif ⌿KX(E/D), in which ⌿ corresponds to a hydrophobic residue.Although E1 and E2 are sufficient for SUMO conjugation to various substrates (8, 9), it is assumed that SUMO E3 ligases catalyze sumoylation at non-consensus sites, increase the rate of modification, or ensure substrate specificity (10 -13). Sumoylation is a highly dynamic and reversible process as specific proteases can rapidly remove SUMO from their substrates (for review, see Ref.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Small Ubiquitin-like Modifier (SUMO) Modification of Natively Unfolded Proteins Tau and α-Synuclein

Dorval

Fraser

2006

Journal of Biological Chemistry

263

281

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“…In line with this view, parkin, a ubiquitin E3 ligase relevant to mitophagy, has been shown to be positive in some GCI-positive oligodendroglia [27]. In addition, small ubiquitin-like modifier type 1 (SUMO-1), which regulates DRP1 activity, is also positive in some GCIs [42]. Therefore, it is possible that our finding of substantial DRP1 immunoreactivity in GCI-containing oligodendroglia reflects abnormal mitochondrial fission leading to mitochondrial fragmentation and mitophagy.…”

Section: Discussionsupporting

confidence: 65%

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Ota

Obayashi

Ozaki

et al. 2014

Acta Neuropathologica Communications

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Abstractp25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N-and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated α-synuclein (pα-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.

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“…Other experimental evidence suggests that increased SUMO-3 SUMOylation is correlated to the downregulation of amyloid b peptide production in cell culture, implicating the SUMO pathway in the onset or progression of Alzheimer's disease (61). Moreover, SUMO-1 has been found within the a-synuclein-positive cytoplasmic aggregates in the brain tissue in multiple system atrophy and dementia with Lewy bodies (62,63). Another recent study has shown that the E3 ubiquitin ligase activity of Parkin and its intracellular localization may be modulated by SUMO-1 association (64).…”

Section: Senps and Diseasesmentioning

confidence: 99%

DeSUMOylating enzymes—SENPs

Drąg

Salvesen

2008

IUBMB Life

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SummaryModification of proteins by ubiquitin and SUMO (small ubiquitin-like modifiers) is a dynamic and reversible process. Similar to the ubiquitin pathway, where the action of deubiquitinating enzymes removes ubiquitin from ubiquitin-adducts, SUMO is also removed intact from its substrates by proteases belonging to the sentrin-specific proteases (SENPs) family. In addition to their isopeptidase activity, SENPs also execute another essential function as endopeptidases by removing the short C-terminal extension from immature SUMOs. The defining characteristics of SENPs are their predicted conserved molecular scaffold-defined as members of peptidase Clan CE, conserved catalytic mechanism, and their reported activity on SUMO or Nedd8 conjugated proteins (or the respective precursors). We discuss recent progress on the human SENPs and their substrates. IUBMBIUBMB Life, 60(11): 734-742, 2008

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SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy

Cited by 58 publications

References 32 publications

Small Ubiquitin-like Modifier (SUMO) Modification of Natively Unfolded Proteins Tau and α-Synuclein

Small Ubiquitin-like Modifier (SUMO) Modification of Natively Unfolded Proteins Tau and α-Synuclein

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

DeSUMOylating enzymes—SENPs

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