Abstract
Posttranslational modifications are ubiquitous regulators of cellular processes. The regulatory role of SUMOylation, the attachment of a small ubiquitin-related modifier to a target protein, has been implicated in fundamental processes like cell division, DNA damage repair, mitochondrial homeostasis, and stress responses. Recently, it is gaining more attention in drug discovery as well. As life expectancy keeps rising, more individuals are at risk for developing age-associated diseases. This not only makes a person’s life uncomfortable, but it also places an economic burden on society. Therefore, finding treatments for age-related diseases is an important issue. Understanding the basic mechanisms in the cell under normal and disease conditions is fundamental for drug discovery. There is an increasing number of reports showing that the ageing process could be influenced by SUMOylation. Similarly, SUMOylation is essential for proper neuronal function. In this review we summarize the latest results regarding the connection between SUMOylation and neurodegenerative diseases. We highlight the significance of specific SUMO target proteins and the importance of SUMO isoform specificity.
References
1.
2.
Wilkinson
KA
, Henley
JM
. Mechanisms, regulation and consequences of protein SUMOylation
. Biochem J
. 2010
May
;428
(2
):133
–45
.
[PubMed]
0264-60213.
Geiss-Friedlander
R
, Melchior
F
. Concepts in sumoylation: a decade on
. Nat Rev Mol Cell Biol
. 2007
Dec
;8
(12
):947
–56
.
[PubMed]
1471-00724.
Shin
EJ
, Shin
HM
, Nam
E
, Kim
WS
, Kim
JH
, Oh
BH
, et al. DeSUMOylating isopeptidase: a second class of SUMO protease
. EMBO Rep
. 2012
Apr
;13
(4
):339
–46
.
[PubMed]
1469-221X5.
Schulz
S
, Chachami
G
, Kozaczkiewicz
L
, Winter
U
, Stankovic-Valentin
N
, Haas
P
, et al. Ubiquitin-specific protease-like 1 (USPL1) is a SUMO isopeptidase with essential, non-catalytic functions
. EMBO Rep
. 2012
Oct
;13
(10
):930
–8
.
[PubMed]
1469-221X6.
Flotho
A
, Melchior
F
. Sumoylation: a regulatory protein modification in health and disease
. Annu Rev Biochem
. 2013
;82
(1
):357
–85
.
[PubMed]
0066-41547.
Psakhye
I
, Jentsch
S
. Protein group modification and synergy in the SUMO pathway as exemplified in DNA repair
. Cell
. 2012
Nov
;151
(4
):807
–20
.
[PubMed]
0092-86748.
Lallemand-Breitenbach
V
, de Thé
H
. PML nuclear bodies: from architecture to function
. Curr Opin Cell Biol
. 2018
Jun
;52
:154
–61
.
[PubMed]
0955-06749.
Schwertman
P
, Bekker-Jensen
S
, Mailand
N
. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers
. Nat Rev Mol Cell Biol
. 2016
May
;17
(6
):379
–94
.
[PubMed]
1471-007210.
Gill
G
. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?
Genes Dev
. 2004
Sep
;18
(17
):2046
–59
.
[PubMed]
0890-936911.
Sriramachandran
AM
, Dohmen
RJ
. SUMO-targeted ubiquitin ligases
. Biochim Biophys Acta
. 2014
Jan
;1843
(1
):75
–85
.
[PubMed]
0006-300212.
Guo
D
, Li
M
, Zhang
Y
, Yang
P
, Eckenrode
S
, Hopkins
D
, et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes
. Nat Genet
. 2004
Aug
;36
(8
):837
–41
.
[PubMed]
1061-403613.
Baczyk
D
, Audette
MC
, Drewlo
S
, Levytska
K
, Kingdom
JC
. SUMO-4: A novel functional candidate in the human placental protein SUMOylation machinery
. PLoS One
. 2017
May
;12
(5
):e0178056
.
[PubMed]
1932-620314.
Enserink
JM
. Regulation of Cellular Processes by SUMO: understudied Topics
. Adv Exp Med Biol
. 2017
;963
:89
–97
.
[PubMed]
0065-259815.
Liebelt
F
, Vertegaal
AC
. Ubiquitin-dependent and independent roles of SUMO in proteostasis
. Am J Physiol Cell Physiol
. 2016
Aug
;311
(2
):C284
–96
.
[PubMed]
0363-614316.
Henley
JM
, Carmichael
RE
, Wilkinson
KA
. Extranuclear SUMOylation in Neurons
. Trends Neurosci
. 2018
Apr
;41
(4
):198
–210
.
[PubMed]
0166-223617.
Seeler
JS
, Dejean
A
. SUMO and the robustness of cancer
. Nat Rev Cancer
. 2017
Mar
;17
(3
):184
–97
.
[PubMed]
1474-175X18.
Abe
JI
, Sandhu
UG
, Hoang
NM
, Thangam
M
, Quintana-Quezada
RA
, Fujiwara
K
, et al. Coordination of Cellular Localization-Dependent Effects of Sumoylation in Regulating Cardiovascular and Neurological Diseases
. Adv Exp Med Biol
. 2017
;963
:337
–58
.
[PubMed]
0065-259819.
Princz
A
, Tavernarakis
N
. The role of SUMOylation in ageing and senescent decline
. Mech Ageing Dev
. 2017
Mar
;162
:85
–90
.
[PubMed]
0047-637420.
Gong
L
, Sun
Q
, Li
DW
. Sumoylation in Cellular Senescence and Aging
. Curr Mol Med
. 2017
;16
(10
):871
–6
.
[PubMed]
1566-524021.
Scurr
LL
, Haferkamp
S
, Rizos
H
. The Role of Sumoylation in Senescence
. Adv Exp Med Biol
. 2017
;963
:215
–26
.
[PubMed]
0065-259822.
Yang
QG
, Wang
F
, Zhang
Q
, Xu
WR
, Chen
YP
, Chen
GH
. Correlation of increased hippocampal Sumo3 with spatial learning ability in old C57BL/6 mice
. Neurosci Lett
. 2012
Jun
;518
(2
):75
–9
.
[PubMed]
0304-394023.
Datwyler
AL
, Lättig-Tünnemann
G
, Yang
W
, Paschen
W
, Lee
SL
, Dirnagl
U
, et al. SUMO2/3 conjugation is an endogenous neuroprotective mechanism
. J Cereb Blood Flow Metab
. 2011
Nov
;31
(11
):2152
–9
.
[PubMed]
0271-678X24.
Ficulle
E
, Sufian
MD
, Tinelli
C
, Corbo
M
, Feligioni
M
. Aging-related SUMOylation pattern in the cortex and blood plasma of wild type mice
. Neurosci Lett
. 2018
Mar
;668
:48
–54
.
[PubMed]
0304-394025.
Stankova
T
, Piepkorn
L
, Bayer
TA
, Jahn
O
, Tirard
M
. SUMO1-conjugation is altered during normal aging but not by increased amyloid burden
. Aging Cell
. 2018
Aug
;17
(4
):e12760
.
[PubMed]
1474-971826.
Zhang
FP
, Mikkonen
L
, Toppari
J
, Palvimo
JJ
, Thesleff
I
, Jänne
OA
. Sumo-1 function is dispensable in normal mouse development
. Mol Cell Biol
. 2008
Sep
;28
(17
):5381
–90
.
[PubMed]
0270-730627.
Wang
L
, Wansleeben
C
, Zhao
S
, Miao
P
, Paschen
W
, Yang
W
. SUMO2 is essential while SUMO3 is dispensable for mouse embryonic development
. EMBO Rep
. 2014
Aug
;15
(8
):878
–85
.
[PubMed]
1469-221X28.
Matsuzaki
S
, Lee
L
, Knock
E
, Srikumar
T
, Sakurai
M
, Hazrati
LN
, et al. SUMO1 Affects Synaptic Function, Spine Density and Memory
. Sci Rep
. 2015
May
;5
(1
):10730
.
[PubMed]
2045-232229.
Zhang
L
, Liu
X
, Sheng
H
, Liu
S
, Li
Y
, Zhao
JQ
, et al. Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice
. Neuroscience
. 2017
Feb
;343
:190
–212
.
[PubMed]
0306-452230.
Henley
JM
, Craig
TJ
, Wilkinson
KA
. Neuronal SUMOylation: mechanisms, physiology, and roles in neuronal dysfunction
. Physiol Rev
. 2014
Oct
;94
(4
):1249
–85
.
[PubMed]
0031-933331.
Schorova L, Martin S. Sumoylation in Synaptic Function and Dysfunction. Front Synaptic Neurosci. 2016 Apr;8:9.
32.
Daniel
JA
, Cooper
BH
, Palvimo
JJ
, Zhang
FP
, Brose
N
, Tirard
M
. Response: Commentary: Analysis of SUMO1-conjugation at synapses
. Front Cell Neurosci
. 2018
May
;12
:117
.
[PubMed]
1662-510233.
Spires-Jones
TL
, Hyman
BT
. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease
. Neuron
. 2014
May
;82
(4
):756
–71
.
[PubMed]
0896-627334.
Li
Y
, Wang
H
, Wang
S
, Quon
D
, Liu
YW
, Cordell
B
. Positive and negative regulation of APP amyloidogenesis by sumoylation
. Proc Natl Acad Sci USA
. 2003
Jan
;100
(1
):259
–64
.
[PubMed]
0027-842435.
Dorval
V
, Mazzella
MJ
, Mathews
PM
, Hay
RT
, Fraser
PE
. Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins
. Biochem J
. 2007
Jun
;404
(2
):309
–16
.
[PubMed]
0264-602136.
Zhang
YQ
, Sarge
KD
. Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels
. Biochem Biophys Res Commun
. 2008
Oct
;374
(4
):673
–8
.
[PubMed]
0006-291X37.
Yun
SM
, Cho
SJ
, Song
JC
, Song
SY
, Jo
SA
, Jo
C
, et al. SUMO1 modulates Aβ generation via BACE1 accumulation
. Neurobiol Aging
. 2013
Mar
;34
(3
):650
–62
.
[PubMed]
0197-458038.
Nisticò
R
, Ferraina
C
, Marconi
V
, Blandini
F
, Negri
L
, Egebjerg
J
, et al. Age-related changes of protein SUMOylation balance in the AβPP Tg2576 mouse model of Alzheimer’s disease
. Front Pharmacol
. 2014
Apr
;5
:63
.
[PubMed]
1663-981239.
Tao
CC
, Hsu
WL
, Ma
YL
, Cheng
SJ
, Lee
EH
. Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease
. Cell Death Differ
. 2017
Apr
;24
(4
):597
–614
.
[PubMed]
1350-904740.
Knock
E
, Matsuzaki
S
, Takamura
H
, Satoh
K
, Rooke
G
, Han
K
, et al. SUMO1 impact on Alzheimer disease pathology in an amyloid-depositing mouse model
. Neurobiol Dis
. 2018
Feb
;110
:154
–65
.
[PubMed]
0969-996141.
Maruyama
T
, Abe
Y
, Niikura
T
. SENP1 and SENP2 regulate SUMOylation of amyloid precursor protein
. Heliyon
. 2018
Apr
;4
(4
):e00601
.
[PubMed]
2405-844042.
Marcelli
S
, Ficulle
E
, Iannuzzi
F
, Kövari
E
, Nisticò
R
, Feligioni
M
. Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer’s Disease
. Mol Neurobiol
. 2017
Oct
;54
(8
):6609
–23
.
[PubMed]
0893-764843.
Baas
, P.W.
and L.
Qiang
, Tau: It's Not What You Think. Trends Cell Biol, 2019
.44.
Dorval
V
, Fraser
PE
. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein
. J Biol Chem
. 2006
Apr
;281
(15
):9919
–24
.
[PubMed]
0021-925845.
Takahashi
K
, Ishida
M
, Komano
H
, Takahashi
H
. SUMO-1 immunoreactivity co-localizes with phospho-Tau in APP transgenic mice but not in mutant Tau transgenic mice
. Neurosci Lett
. 2008
Aug
;441
(1
):90
–3
.
[PubMed]
0304-394046.
Luo
HB
, Xia
YY
, Shu
XJ
, Liu
ZC
, Feng
Y
, Liu
XH
, et al. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination
. Proc Natl Acad Sci USA
. 2014
Nov
;111
(46
):16586
–91
.
[PubMed]
0027-842447.
Vijayakumaran
S
, Wong
MB
, Antony
H
, Pountney
DL
. Direct and/or Indirect Roles for SUMO in Modulating Alpha-Synuclein Toxicity
. Biomolecules
. 2015
Jul
;5
(3
):1697
–716
.
[PubMed]
2218-273X48.
Calo
L
, Wegrzynowicz
M
, Santivañez-Perez
J
, Grazia Spillantini
M
. Synaptic failure and α-synuclein
. Mov Disord
. 2016
Feb
;31
(2
):169
–77
.
[PubMed]
0885-318549.
Peng
, C.
, R.J.
Gathagan
, and V.M.
Lee
, Distinct alpha-Synuclein strains and implications for heterogeneity among alpha-Synucleinopathies.
Neurobiol Dis, 2018
. 109(Pt B): p. 209-218.50.
Krumova
P
, Meulmeester
E
, Garrido
M
, Tirard
M
, Hsiao
HH
, Bossis
G
, et al. Sumoylation inhibits alpha-synuclein aggregation and toxicity
. J Cell Biol
. 2011
Jul
;194
(1
):49
–60
.
[PubMed]
0021-952551.
Oh
Y
, Kim
YM
, Mouradian
MM
, Chung
KC
. Human Polycomb protein 2 promotes α-synuclein aggregate formation through covalent SUMOylation
. Brain Res
. 2011
Mar
;1381
:78
–89
.
[PubMed]
0006-899352.
Kim
YM
, Jang
WH
, Quezado
MM
, Oh
Y
, Chung
KC
, Junn
E
, et al. Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation
. J Neurol Sci
. 2011
Aug
;307
(1-2
):157
–61
.
[PubMed]
0022-510X53.
Rott
R
, Szargel
R
, Shani
V
, Hamza
H
, Savyon
M
, Abd Elghani
F
, et al. SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation
. Proc Natl Acad Sci USA
. 2017
Dec
;114
(50
):13176
–81
.
[PubMed]
0027-842454.
Kunadt
M
, Eckermann
K
, Stuendl
A
, Gong
J
, Russo
B
, Strauss
K
, et al. Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation
. Acta Neuropathol
. 2015
May
;129
(5
):695
–713
.
[PubMed]
0001-632255.
Um
JW
, Chung
KC
. Functional modulation of parkin through physical interaction with SUMO-1
. J Neurosci Res
. 2006
Nov
;84
(7
):1543
–54
.
[PubMed]
0360-401256.
Eckermann
K
. SUMO and Parkinson’s disease
. Neuromolecular Med
. 2013
Dec
;15
(4
):737
–59
.
[PubMed]
1535-108457.
Shinbo
Y
, Niki
T
, Taira
T
, Ooe
H
, Takahashi-Niki
K
, Maita
C
, et al. Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities
. Cell Death Differ
. 2006
Jan
;13
(1
):96
–108
.
[PubMed]
1350-904758.
Ross
CA
, Tabrizi
SJ
. Huntington’s disease: from molecular pathogenesis to clinical treatment
. Lancet Neurol
. 2011
Jan
;10
(1
):83
–98
.
[PubMed]
1474-442259.
Steffan
JS
, Agrawal
N
, Pallos
J
, Rockabrand
E
, Trotman
LC
, Slepko
N
, et al. SUMO modification of Huntingtin and Huntington’s disease pathology
. Science
. 2004
Apr
;304
(5667
):100
–4
.
[PubMed]
0036-807560.
O’Rourke
JG
, Gareau
JR
, Ochaba
J
, Song
W
, Raskó
T
, Reverter
D
, et al. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation
. Cell Rep
. 2013
Jul
;4
(2
):362
–75
.
[PubMed]
2639-185661.
Ochaba
J
, Monteys
AM
, O’Rourke
JG
, Reidling
JC
, Steffan
JS
, Davidson
BL
, et al. PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo
. Neuron
. 2016
May
;90
(3
):507
–20
.
[PubMed]
0896-627362.
Ohkuni K, Pasupala N, Peek J, Holloway GL, Sclar GD, Levy-Myers R, et al. SUMO-Targeted Ubiquitin Ligases (STUbLs) Reduce the Toxicity and Abnormal Transcriptional Activity Associated With a Mutant, Aggregation-Prone Fragment of Huntingtin. Front Genet. 2018 Sep;9:379.
63.
Kho
C
, Lee
A
, Jeong
D
, Oh
JG
, Gorski
PA
, Fish
K
, et al. Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
. Nat Commun
. 2015
Jun
;6
(1
):7229
.
[PubMed]
2041-172364.
He
X
, Riceberg
J
, Soucy
T
, Koenig
E
, Minissale
J
, Gallery
M
, et al. Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor
. Nat Chem Biol
. 2017
Nov
;13
(11
):1164
–71
.
[PubMed]
1552-445065.
Yavvari
PS
, Verma
P
, Mustfa
SA
, Pal
S
, Kumar
S
, Awasthi
AK
, et al. A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation
. Nanoscale
. 2019
Mar
;11
(11
):4970
–86
.
[PubMed]
2040-336466.
Hughes
DJ
, Tiede
C
, Penswick
N
, Tang
AA
, Trinh
CH
, Mandal
U
, et al. Generation of specific inhibitors of SUMO-1- and SUMO-2/3-mediated protein-protein interactions using Affimer (Adhiron) technology
. Sci Signal
. 2017
Nov
;10
(505
):eaaj2005
.
[PubMed]
1945-0877© 2019 S. Karger AG, Basel
2019
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
