Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease.
Animals
Disease Models, Animal
Drosophila Proteins
/ genetics
Drosophila melanogaster
/ genetics
Humans
Light
Loss of Function Mutation
/ genetics
Mitochondria
/ genetics
Neurons
/ metabolism
Optogenetics
/ methods
Parkinson Disease
/ genetics
Phosphatidylinositol 3-Kinases
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Retina
/ growth & development
Signal Transduction
/ genetics
Transfection
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
07
12
2020
accepted:
10
03
2021
entrez:
15
4
2021
pubmed:
16
4
2021
medline:
26
8
2021
Statut:
epublish
Résumé
Optogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson's disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to inspire novel strategies towards a spatio-temporal regulation of tissue repair.
Identifiants
pubmed: 33857132
doi: 10.1371/journal.pgen.1009479
pii: PGENETICS-D-20-01847
pmc: PMC8049241
doi:
Substances chimiques
Drosophila Proteins
0
PINK1 protein, Drosophila
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009479Subventions
Organisme : Austrian Science Fund FWF
ID : W 1232
Pays : Austria
Déclaration de conflit d'intérêts
The authors declare that they have no conflict of interest.
Références
Biochem Soc Trans. 2015 Apr;43(2):275-9
pubmed: 25849929
Science. 2012 Jun 8;336(6086):1306-10
pubmed: 22582012
FEBS Lett. 2015 Dec 21;589(24 Pt A):3760-72
pubmed: 26555190
Recent Results Cancer Res. 1998;154:229-36
pubmed: 10027003
Nat Methods. 2010 Nov;7(11):897-900
pubmed: 20881965
Science. 2018 Aug 31;361(6405):
pubmed: 30166458
FEBS Lett. 2005 Jul 4;579(17):3789-96
pubmed: 15978587
Nat Chem Biol. 2009 Nov;5(11):827-34
pubmed: 19718042
Elife. 2016 Jan 12;5:e11860
pubmed: 26754770
Sci Rep. 2014 Dec 09;4:7383
pubmed: 25488603
Hum Mol Genet. 2005 Mar 15;14(6):799-811
pubmed: 15689351
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8
pubmed: 16818890
Mol Cell Biol. 1996 Mar;16(3):1058-65
pubmed: 8622650
Nat Chem Biol. 2006 Nov;2(11):636-44
pubmed: 17013378
Nat Biotechnol. 2015 Feb;33(2):204-9
pubmed: 25580598
Proc R Soc Lond B Biol Sci. 1978 Mar 22;200(1141):441-61
pubmed: 26058
J Parkinsons Dis. 2018;8(2):195-215
pubmed: 29710735
J Mol Biol. 2020 Jun 12;432(13):3761-3770
pubmed: 32422149
Exp Neurol. 2002 Oct;177(2):461-74
pubmed: 12429192
Dev Cell. 2015 Dec 7;35(5):646-660
pubmed: 26777292
Development. 2018 Feb 2;145(3):
pubmed: 29361562
Nat Rev Neurosci. 2012 Mar 20;13(4):251-66
pubmed: 22430017
Nat Chem Biol. 2015 Dec;11(12):952-4
pubmed: 26457372
Nat Cell Biol. 2010 Jun;12(6):591-7
pubmed: 20473296
J Neurosci. 2015 Oct 21;35(42):14370-85
pubmed: 26490873
J Clin Invest. 2015 May;125(5):1873-85
pubmed: 25822020
Curr Opin Biotechnol. 2018 Aug;52:42-48
pubmed: 29505976
J Biol Chem. 2009 Aug 21;284(34):22938-51
pubmed: 19546216
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19625-30
pubmed: 18003911
Cell. 2001 Mar 9;104(5):699-708
pubmed: 11257224
Cell. 1996 Jun 28;85(7):1113-24
pubmed: 8674117
Nat Rev Cancer. 2014 Mar;14(3):173-86
pubmed: 24561444
Cell. 1991 Mar 22;64(6):1069-81
pubmed: 2004416
Ann Neurol. 2015 Aug;78(2):248-57
pubmed: 26061140
Physiol Rev. 2020 Oct 1;100(4):1467-1525
pubmed: 32191560
Cell Rep. 2016 Jul 19;16(3):866-77
pubmed: 27396324
Science. 2010 Jul 23;329(5990):413-7
pubmed: 20576849
Brain. 2017 Jan;140(1):98-117
pubmed: 27807026
Brain Res. 2000 Dec 15;886(1-2):82-98
pubmed: 11119690
Vis Neurosci. 1996 Jan-Feb;13(1):15-30
pubmed: 8730986
J Vis Exp. 2011 Mar 11;(49):
pubmed: 21445036
Mol Cell Biol. 1995 Mar;15(3):1613-9
pubmed: 7532281
PLoS Genet. 2014 Nov 20;10(11):e1004815
pubmed: 25412178
Nat Neurosci. 2015 Sep;18(9):1213-25
pubmed: 26308982
Science. 2009 Apr 17;324(5925):354-9
pubmed: 19299587
Science. 2014 Apr 11;344(6180):203-7
pubmed: 24652937
Curr Opin Biotechnol. 2017 Dec;48:8-14
pubmed: 28273648
Lancet Neurol. 2010 Dec;9(12):1164-1172
pubmed: 20970382
Mov Disord. 2015 Nov;30(13):1715-24
pubmed: 26769457
Curr Top Dev Biol. 2017;121:173-200
pubmed: 28057299
Dev Biol. 1989 Dec;136(2):346-62
pubmed: 2511048
Cell. 1985 Sep;42(2):581-8
pubmed: 2992805
Nature. 2006 Jun 29;441(7097):1162-6
pubmed: 16672981
Chem Biol. 2014 Jul 17;21(7):903-12
pubmed: 24981772
J Biol Chem. 2001 Aug 24;276(34):31845-50
pubmed: 11435419
J Cell Biol. 2017 Mar 6;216(3):695-708
pubmed: 28137779
Development. 1998 Jun;125(12):2327-35
pubmed: 9584131
Structure. 2012 Apr 4;20(4):698-706
pubmed: 22483116
Nature. 2006 Jun 29;441(7097):1157-61
pubmed: 16672980
Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6400-5
pubmed: 23509287
Dev Cell. 2017 Jan 23;40(2):185-192
pubmed: 28118601
J Mol Biol. 2020 May 1;432(10):3159-3176
pubmed: 32201167
Mol Ther. 2009 Jun;17(6):980-91
pubmed: 19277011
Development. 2016 Nov 1;143(21):4085-4094
pubmed: 27697903
Neural Regen Res. 2017 Aug;12(8):1197-1209
pubmed: 28966628
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83
pubmed: 12642658
EMBO J. 2014 Feb 18;33(4):341-55
pubmed: 24473149
Endocrinology. 1994 Apr;134(4):1879-87
pubmed: 8137756
J Biol Chem. 2012 Jan 13;287(3):1932-45
pubmed: 22128160
Cell. 1996 Nov 15;87(4):651-60
pubmed: 8929534
Neuron. 2001 Jan;29(1):171-84
pubmed: 11182089
Nat Methods. 2010 Dec;7(12):973-5
pubmed: 21037589
Genetics. 2005 Nov;171(3):1057-81
pubmed: 15965261
Biomed Opt Express. 2015 Jan 13;6(2):514-23
pubmed: 25780741
Science. 2004 May 21;304(5674):1158-60
pubmed: 15087508
J Biol Chem. 2005 Nov 4;280(44):36584-91
pubmed: 16123037
Mol Cell Biol. 2003 Apr;23(7):2251-63
pubmed: 12640111
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13520-5
pubmed: 16938835
Ann Neurol. 2004 Sep;56(3):336-41
pubmed: 15349860
J Cell Biol. 2018 May 7;217(5):1613-1622
pubmed: 29500189
Mol Cell. 2017 Sep 7;67(5):757-769.e5
pubmed: 28826673
Front Neuroanat. 2017 Apr 10;11:29
pubmed: 28442998
Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25756-25763
pubmed: 31796593
J Neurosci. 2000 Jun 15;20(12):4686-700
pubmed: 10844038
Biophys J. 2011 Jun 8;100(11):2801-9
pubmed: 21641326
J Clin Invest. 2005 Jun;115(6):1627-35
pubmed: 15902306
Trends Cell Biol. 2016 Nov;26(11):864-874
pubmed: 27727011
Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1053-8
pubmed: 11158593
Neurobiol Dis. 2016 Apr;88:44-54
pubmed: 26777664
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42
pubmed: 9724721
Genet Mol Res. 2003 Mar 31;2(1):43-7
pubmed: 12917801
J Neurochem. 2016 Oct;139 Suppl 1:232-239
pubmed: 27251035
EMBO J. 2014 Aug 1;33(15):1713-26
pubmed: 24986882
Science. 2014 Apr 4;344(6179):94-7
pubmed: 24700859
Development. 1998 Aug;125(16):3037-48
pubmed: 9671578
Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):272-7
pubmed: 21173233
Angew Chem Int Ed Engl. 2016 May 17;55(21):6339-42
pubmed: 27101018
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):701-6
pubmed: 9012848
Mech Dev. 1994 Feb;45(2):139-45
pubmed: 8199050
Neuron. 2018 Jun 27;98(6):1155-1169.e6
pubmed: 29887339