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Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Perny Michael, Muri Lukas, Dawson Heather, Kleinlogel Sonja,
Project Next-generation optogenetics to cure blindness
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Original article (peer-reviewed)

Journal Cell Death and Disease
Volume (Issue) 7
Page(s) e2447
Title of proceedings Cell Death and Disease

Open Access

URL https://www.ncbi.nlm.nih.gov/pubmed/27809305
Type of Open Access Publisher (Gold Open Access)

Abstract

Channelrhodopsin-2 (ChR2) has become a celebrated research tool and is considered a promising potential therapeutic for neurological disorders. While making its way into the clinic, concerns about the safety of chronic ChR2 activation have emerged; in particular as the high-intensity blue light illumination needed for ChR2 activation may be phototoxic. Here we set out to quantify for the first time the cytotoxic effects of chronic ChR2 activation. We studied the safety of prolonged illumination on ChR2(D156A)-expressing human melanoma cells as cancer cells are notorious for their resistance to killing. Three days of illumination eradicated the entire ChR2(D156A)-expressing cell population through mitochondria-mediated apoptosis, whereas blue light activation of non-expressing control cells did not significantly compromise cell viability. In other words, chronic high-intensity blue light illumination alone is not phototoxic, but prolonged ChR2 activation induces mitochondria-mediated apoptosis. The results are alarming for gain-of-function translational neurological studies but open the possibility to optogenetically manipulate the viability of non-excitable cells, such as cancer cells. In a second set of experiments we therefore evaluated the feasibility to put melanoma cell proliferation and apoptosis under the control of light by transdermally illuminating in vivo melanoma xenografts expressing ChR2(D156A). We show clear proof of principle that light treatment inhibits and even reverses tumor growth, rendering ChR2s potential tools for targeted light-therapy of cancers.
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