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

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.

Optimized design and in vivo application of optogenetically functionalized Drosophila dopamine receptors

“…The high light sensitivity of the Rho backbone enables the activation of our optoXRs with blue or green light in adult flies in vivo despite less than 6% light penetrance of the adult cuticle in this spectral range 78 , 86 . Although Rho is known to inactivate after its light cycle and only slowly being recycled 87 , we did not observe a run-down in functionality in vitro or in vivo, possibly due to the abundance of the expressed optoXRs and the supplemented 9- cis -retinal.…”

Invertebrate genetic models of amyotrophic lateral sclerosis

“…Similarly, optogenetic methods may be used in ALS models, including in vivo and in vitro models, to study the pathogenesis, pathology, and potential treatments for ALS. The use of invertebrate models to develop novel genetic and optogenetic strategies to investigate the pathological mechanisms of ALS is a promising research tool (Ingles-Prieto et al, 2021 ).…”

Regenerative Strategies for Retinal Neurons: Novel Insights in Non-Mammalian Model Organisms

“…In particular, the optogenetic activation of both the Raf/MEK/ERK (optoRaf) and AKT (optoAKT) signaling enhanced axon regeneration in injured neurons, but only optoRaf improved dendritic branching in CNS and the peripheral nervous system. Accordingly, it was recently reported that the optogenetics approach may induce beneficial trophic effects in a fly genetic model for parkinsonism [ 59 ]. Therefore, because of its simple genetic manipulation, D. melanogaster represents an ideal animal model to expand research in optogenetics and provide proof-of-concept studies.…”