Parkinson mice show functional and molecular changes in the gut long before motoric disease onset.
Early onset
Enteric nervous system
Gastrointestinal motility
Parkinson’s disease
Protein-and miRNA biomarkers
Journal
Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600
Informations de publication
Date de publication:
02 06 2021
02 06 2021
Historique:
received:
25
09
2020
accepted:
03
03
2021
entrez:
3
6
2021
pubmed:
4
6
2021
medline:
11
1
2022
Statut:
epublish
Résumé
There is increasing evidence that Parkinson's disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest. Based on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS. A retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model. These findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.
Sections du résumé
BACKGROUND
There is increasing evidence that Parkinson's disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest.
METHODS
Based on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS.
RESULTS
A retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model.
CONCLUSIONS
These findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.
Identifiants
pubmed: 34078425
doi: 10.1186/s13024-021-00439-2
pii: 10.1186/s13024-021-00439-2
pmc: PMC8170976
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
34Références
Science. 2010 Sep 24;329(5999):1663-7
pubmed: 20798282
Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):E1028-37
pubmed: 25691754
J Biol Chem. 2008 Apr 4;283(14):9089-100
pubmed: 18245082
PLoS One. 2018 Apr 2;13(4):e0195339
pubmed: 29608598
Front Neurosci. 2020 Mar 31;14:213
pubmed: 32296300
Biochem J. 2017 Apr 13;474(9):1439-1451
pubmed: 28408429
Brain. 2020 Oct 1;143(10):3077-3088
pubmed: 32830221
J Parkinsons Dis. 2019;9(s2):S281-S295
pubmed: 31498132
J Neurosci. 2000 Apr 1;20(7):RC67
pubmed: 10729356
Acta Neuropathol. 2012 May;123(5):653-69
pubmed: 22361813
J Neurol. 2013 May;260(5):1332-8
pubmed: 23263478
Biochemistry. 2007 Jan 16;46(2):472-82
pubmed: 17209557
Prog Clin Biol Res. 1989;317:809-18
pubmed: 2557642
Nature. 2000 Sep 14;407(6801):153-9
pubmed: 11001046
Mol Cell Biochem. 1992 Jun 26;112(2):181-6
pubmed: 1322491
J Pathol. 1988 May;155(1):9-15
pubmed: 2837558
Ageing Res Rev. 2020 Jan;57:100997
pubmed: 31816444
Parkinsonism Relat Disord. 2016 Nov;32:66-72
pubmed: 27591074
Acta Neuropathol. 1990;79(6):581-3
pubmed: 1972853
J Neuropathol Exp Neurol. 2017 Apr 1;76(4):270-288
pubmed: 28340083
J Neurochem. 1989 Feb;52(2):381-9
pubmed: 2911023
J Chem Neuroanat. 2014 Nov;61-62:20-32
pubmed: 25014433
Front Neurosci. 2019 May 10;13:457
pubmed: 31133790
Science. 2015 Mar 27;347(6229):1441-1446
pubmed: 25814576
Sci Rep. 2015 Mar 20;5:9226
pubmed: 25791532
Sci Rep. 2016 Sep 15;6:33289
pubmed: 27628239
Brain Behav. 2018 Feb 19;8(4):e00941
pubmed: 29670823
Ann Neurol. 1992;32 Suppl:S88-93
pubmed: 1510386
Funct Neurol. 2017 Jan/Mar;32(1):28-34
pubmed: 28380321
Arch Neurol. 1998 Feb;55(2):151-2
pubmed: 9482355
Mov Disord. 2012 May;27(6):708
pubmed: 22649005
Neuropathology. 2018 Dec;38(6):583-590
pubmed: 30215870
J Innate Immun. 2018;10(3):172-180
pubmed: 29742516
Exp Neurol. 2000 Aug;164(2):322-32
pubmed: 10915571
Skelet Muscle. 2018 Sep 19;8(1):30
pubmed: 30231928
J Biomed Inform. 2011 Oct;44(5):839-47
pubmed: 21605702
Curr Mol Med. 2015;15(2):146-67
pubmed: 25732149
Trends Neurosci. 1989 Nov;12(11):417-20
pubmed: 2479140
Neurogastroenterol Motil. 2019 May;31(5):e13560
pubmed: 30761698
Genet Mol Biol. 2019 Jan-Mar;42(1):40-47
pubmed: 30672978
Exp Brain Res. 2017 Dec;235(12):3695-3708
pubmed: 28929183
Neurosci Lett. 2006 Mar 20;396(1):67-72
pubmed: 16330147
Mol Biol Rep. 2010 Oct;37(7):3183-92
pubmed: 19826908
Acta Neuropathol. 2014 Dec;128(6):805-20
pubmed: 25296989
Neural Regen Res. 2020 Jun;15(6):1037-1038
pubmed: 31823880
J Comp Neurol. 1993 Mar 15;329(3):328-36
pubmed: 8459049
Parkinsonism Relat Disord. 2018 May;50:104-107
pubmed: 29454662
Mol Cell Proteomics. 2011 Sep;10(9):M110.004739
pubmed: 21610104
Nature. 1997 Aug 28;388(6645):839-40
pubmed: 9278044
Ann Neurol. 2002 Jun;51(6):779-82
pubmed: 12112087
Cell Tissue Res. 2014 Aug;357(2):455-62
pubmed: 24326615
Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
pubmed: 12498954
Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Jun;1863(6):639-650
pubmed: 29571767
Cytoskeleton (Hoboken). 2020 Mar;77(3-4):110-128
pubmed: 31970897
Genes (Basel). 2018 Feb 13;9(2):
pubmed: 29438285
Bioinformatics. 2014 Feb 15;30(4):523-30
pubmed: 24336805
Clin Biochem. 2013 Jul;46(10-11):846-60
pubmed: 23562576
Neurochem Res. 2011 Aug;36(8):1452-63
pubmed: 21484266
Genes Genet Syst. 2019 Apr 27;94(2):61-69
pubmed: 30713215
Neurol India. 2017 Mar-Apr;65(2):263-268
pubmed: 28290386
J Neurosci Res. 1999 Apr 1;56(1):28-35
pubmed: 10213472
Mol Cell Neurosci. 2016 Mar;71:13-24
pubmed: 26658803
J Neural Transm (Vienna). 2018 Mar;125(3):279-290
pubmed: 28168621
J Neural Transm (Vienna). 2003 May;110(5):517-36
pubmed: 12721813
J Neurosci. 2000 Sep 1;20(17):6365-73
pubmed: 10964942
Neurobiol Dis. 2012 Jan;45(1):591-600
pubmed: 22001606
J Dermatol Sci. 2010 Jun;58(3):177-85
pubmed: 20417062
Transl Neurodegener. 2018 Jun 30;7:13
pubmed: 29988485
Lancet Neurol. 2015 Jun;14(6):625-39
pubmed: 25987282
J Neurosci. 2010 Jun 16;30(24):8083-95
pubmed: 20554859
Neurogastroenterol Motil. 2012 Sep;24(9):e425-36
pubmed: 22779732
Hum Mol Genet. 1999 Apr;8(4):567-74
pubmed: 10072423
Mov Disord. 2015 Oct;30(12):1591-601
pubmed: 26474316
Neuron. 2010 Jan 14;65(1):66-79
pubmed: 20152114
N Engl J Med. 1998 Oct 8;339(15):1044-53
pubmed: 9761807
PLoS One. 2018 Oct 18;13(10):e0206239
pubmed: 30335862
Ann Neurol. 1994 Sep;36(3):348-55
pubmed: 8080242
J Auton Nerv Syst. 2000 Jul 3;81(1-3):87-96
pubmed: 10869706
J Neurosci. 2000 May 1;20(9):3214-20
pubmed: 10777786
Acta Neuropathol. 2019 Oct;138(4):535-550
pubmed: 31254094
Diseases. 2019 Feb 05;7(1):
pubmed: 30764502
Neurosci Lett. 1988 May 3;87(3):307-10
pubmed: 3380350
Brain Res Brain Res Protoc. 1997 May;1(2):109-13
pubmed: 9385071
J Neurosci. 2014 Jul 9;34(28):9364-76
pubmed: 25009269
Lancet. 2005 Jan 29-Feb 4;365(9457):412-5
pubmed: 15680456
Brain Res. 1994 Dec 30;668(1-2):62-70
pubmed: 7704619
Nature. 1997 Jan 16;385(6613):265-9
pubmed: 9000076
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
Metab Brain Dis. 2020 Jan;35(1):175-181
pubmed: 31782038
Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4087-92
pubmed: 23431141
Hum Mol Genet. 2010 May 1;19(9):1633-50
pubmed: 20106867
BMC Biochem. 2007 Nov 22;8 Suppl 1:S13
pubmed: 18047737
Biol Chem. 2020 May 26;401(6-7):891-899
pubmed: 32297878
Hum Mol Genet. 2019 Jul 15;28(14):2283-2294
pubmed: 31267130
Gut. 2008 Dec;57(12):1741-3
pubmed: 19022934
Behav Brain Res. 2014 Jun 1;266:37-45
pubmed: 24613235
World J Gastroenterol. 2014 Dec 28;20(48):18216-27
pubmed: 25561789
Science. 2004 May 21;304(5674):1158-60
pubmed: 15087508
Neuroscience. 2019 Mar 1;401:1-10
pubmed: 30660673
Science. 1983 Feb 25;219(4587):979-80
pubmed: 6823561
J Comp Neurol. 1990 May 15;295(3):467-84
pubmed: 2351764
Mov Disord. 1998;13 Suppl 1:35-8
pubmed: 9613716
Elife. 2013 Apr 30;2:e00592
pubmed: 23638301
J Neurochem. 2016 Oct;139 Suppl 1:59-74
pubmed: 27090875
Am J Neurodegener Dis. 2019 Feb 15;8(1):1-15
pubmed: 30906671
Arch Med Res. 2012 Nov;43(8):655-62
pubmed: 23142263
Cell Tissue Res. 2001 Jul;305(1):3-9
pubmed: 11512670
J Cell Biol. 2012 Jan 23;196(2):261-76
pubmed: 22270918
Neurochem Res. 2018 Nov;43(11):2132-2140
pubmed: 30267378
Mov Disord. 2015 Mar;30(3):350-8
pubmed: 25476529
EMBO J. 2018 Sep 14;37(18):
pubmed: 30065071
J Biol Chem. 2012 Nov 16;287(47):39766-75
pubmed: 23033479
Biol Chem. 2019 Aug 27;400(9):1099-1112
pubmed: 31256059
Mol Neurodegener. 2019 Aug 20;14(1):35
pubmed: 31488222
Med Chem. 2016;12(3):217-25
pubmed: 26527155
Cancer Biother Radiopharm. 2018 Apr;33(3):103-109
pubmed: 29641255
Cytoskeleton (Hoboken). 2016 Sep;73(9):477-97
pubmed: 26873625
Trends Neurosci. 1989 Nov;12(11):462-7
pubmed: 2479149
Comp Biochem Physiol A Physiol. 1997 Oct;118(2):331-40
pubmed: 9366065
Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10513-8
pubmed: 18663219
Nat Neurosci. 2020 Mar;23(3):327-336
pubmed: 32066981
Free Radic Biol Med. 2009 Jun 15;46(12):1574-80
pubmed: 19298851
J Parkinsons Dis. 2013;3(4):461-91
pubmed: 24252804
Neurobiol Dis. 2020 Jun;139:104821
pubmed: 32088380
Cells. 2020 Feb 04;9(2):
pubmed: 32033020
J Neurol Sci. 2012 Nov 15;322(1-2):254-62
pubmed: 22669122
Neuron. 1998 Aug;21(2):401-13
pubmed: 9728921
Neurosci Lett. 2017 Sep 29;658:114-120
pubmed: 28823893
Mov Disord Clin Pract. 2019 Aug 26;6(7):547-548
pubmed: 31538088
Genome Biol. 2019 Jan 22;20(1):18
pubmed: 30670076