Increased SUMO-1 expression in the unilateral rotenone-lesioned mouse model of Parkinson's disease

Weetman, Jenna; Wong, Mathew Brendan; Sharry, Stuart Dean; Rcom-H'cheo-Gauthier, Alexandre Nay; Gai, W-P.; Meedeniya, Adrian Cuda Banda; Pountney, Dean L.

doi:10.1016/j.neulet.2013.03.057

Cited by 28 publications

(23 citation statements)

References 28 publications

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“…SUMO1 was also suggested to be present in some Lewy body preparations of PD and DLB brains (24). Unilateral rotenone-lesioned mouse models of PD have increased levels of SUMO1 (44). Our observation of a striking increase in SUMOylated proteins and SUMOylated α-synuclein in PD tissues provides compelling evidence supporting a general up-regulation of SUMOylation in PD and of the SUMOylated α-synuclein in particular.…”

Section: Discussionsupporting

confidence: 59%

SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation

Rott

Szargel

Shani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

141

163

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α-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated α-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in α-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases α-synuclein levels by relieving the inhibition exerted on α-synuclein proteasomal degradation. α-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated α-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of α-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of α-synuclein by PIAS2 promotes α-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on α-synuclein. Second, SUMOylation facilitates α-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of α-synuclein SUMOylation provide a strategy to reduce α-synuclein levels and possibly aggregation in PD.

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Section: Discussionsupporting

confidence: 59%

SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation

Rott

Szargel

Shani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

141

163

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“…These proteins include SUMO, NEDD8, ISG15, FAT10 and Hub1, and have novel functions and influence diverse biological processes. Regarding the link between UBL modification and PD pathogenesis, SUMO-1 expression is increased in the Lewy bodies of PD patient brains as well as in the unilateral rotenone-lesioned mouse model of PD [48,49]. NEDD8 accumulation has also been observed in neuronal and glial inclusions in neurodegenerative disorders [50,51].…”

Section: Discussionmentioning

confidence: 99%

Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin

Yoo

Hyun

et al. 2016

Open Biol.

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Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1, PARK7 (DJ-1), LRRK2 and ATP13A2. Many pathogenic mutations of PARK2, which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis.

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“…Currently however, the mechanisms by which the cytoskeleton deals with these stresses are poorly understood. Indeed, sumoylation is implicated in several neurodegenerative diseases including Alzheimer's [Zhang et al, ; McMillan et al, ; Hoppe et al, ], Parkinson's disease [Kim et al, ; Krumova et al, ; Weetman et al, ], as well as cancer [Lee et al, ; Liu et al, ; Bettermann et al, ], and other diseases [Dorval and Fraser, ; Sarge and Park‐Sarge, ]. However, how sumoylation affects the cytoskeleton in these diseases remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of sumoylation in the regulation of actin, microtubules, intermediate filaments, and septins

et al. 2015

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Sumoylation is a powerful regulatory system that controls many of the critical processes in the cell, including DNA repair, transcriptional regulation, nuclear transport, and DNA replication. Recently, new functions for SUMO have begun to emerge. SUMO is covalently attached to components of each of the four major cytoskeletal networks, including microtubule‐associated proteins, septins, and intermediate filaments, in addition to nuclear actin and actin‐regulatory proteins. However, knowledge of the mechanisms by which this signal transduction system controls the cytoskeleton is still in its infancy. One story that is beginning to unfold is that SUMO may regulate the microtubule motor protein dynein by modification of its adaptor Lis1. In other instances, cytoskeletal elements can both bind to SUMO non‐covalently and also be conjugated by it. The molecular mechanisms for many of these new functions are not yet clear, but are under active investigation. One emerging model links the function of MAP sumoylation to protein degradation through SUMO‐targeted ubiquitin ligases, also known as STUbL enzymes. Other possible functions for cytoskeletal sumoylation are also discussed. © 2015 The Authors. Cytoskeleton Published by Wiley Periodicals, Inc.

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Increased SUMO-1 expression in the unilateral rotenone-lesioned mouse model of Parkinson's disease

Cited by 28 publications

References 28 publications

SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation

SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation

Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin

Emerging roles of sumoylation in the regulation of actin, microtubules, intermediate filaments, and septins

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