Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease

Alvaro Ingles-Prieto, Nikolas Furthmann, Samuel H. Crossman, Alexandra Madelaine Tichy, Nina Hoyer, Meike Petersen, Vanessa Zheden, Julia Biebl, Eva Reichhart, Attila Gyoergy, Daria E. Siekhaus, Peter Soba, Konstanze F. Winklhofer, Harald Janovjak

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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 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.

Original languageEnglish
Article numbere1009479
Number of pages23
JournalPloS Genetics
Volume17
Issue number4 April 2021
DOIs
Publication statusPublished - 15 Apr 2021
Externally publishedYes

Keywords

  • Optogenetic
  • Trophic Signals
  • Parkinson’s Disease

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