In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 17, No. 4 ( 2021-4-15), p. e1009479-
Abstract:
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 PINK1 B9 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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009479
DOI:
10.1371/journal.pgen.1009479.g001
DOI:
10.1371/journal.pgen.1009479.g002
DOI:
10.1371/journal.pgen.1009479.g003
DOI:
10.1371/journal.pgen.1009479.g004
DOI:
10.1371/journal.pgen.1009479.g005
DOI:
10.1371/journal.pgen.1009479.s001
DOI:
10.1371/journal.pgen.1009479.s002
DOI:
10.1371/journal.pgen.1009479.s003
DOI:
10.1371/journal.pgen.1009479.s004
DOI:
10.1371/journal.pgen.1009479.s005
DOI:
10.1371/journal.pgen.1009479.s006
DOI:
10.1371/journal.pgen.1009479.s007
DOI:
10.1371/journal.pgen.1009479.s008
DOI:
10.1371/journal.pgen.1009479.s009
DOI:
10.1371/journal.pgen.1009479.s010
DOI:
10.1371/journal.pgen.1009479.s011
DOI:
10.1371/journal.pgen.1009479.s012
DOI:
10.1371/journal.pgen.1009479.s013
DOI:
10.1371/journal.pgen.1009479.s014
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2186725-2
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