@article{9363,
  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.},
  author       = {Inglés Prieto, Álvaro and Furthmann, Nikolas and Crossman, Samuel H. and Tichy, Alexandra Madelaine and Hoyer, Nina and Petersen, Meike and Zheden, Vanessa and Bicher, Julia and Gschaider-Reichhart, Eva and György, Attila and Siekhaus, Daria E and Soba, Peter and Winklhofer, Konstanze F. and Janovjak, Harald L},
  issn         = {15537404},
  journal      = {PLoS genetics},
  number       = {4},
  pages        = {e1009479},
  publisher    = {Public Library of Science},
  title        = {{Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease}},
  doi          = {10.1371/journal.pgen.1009479},
  volume       = {17},
  year         = {2021},
}

@article{6419,
  abstract     = {Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible.},
  author       = {Pokusaeva, Victoria and Usmanova, Dinara R. and Putintseva, Ekaterina V. and Espinar, Lorena and Sarkisyan, Karen and Mishin, Alexander S. and Bogatyreva, Natalya S. and Ivankov, Dmitry and Akopyan, Arseniy and Avvakumov, Sergey and Povolotskaya, Inna S. and Filion, Guillaume J. and Carey, Lucas B. and Kondrashov, Fyodor},
  issn         = {15537404},
  journal      = {PLoS Genetics},
  number       = {4},
  publisher    = {Public Library of Science},
  title        = {{An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape}},
  doi          = {10.1371/journal.pgen.1008079},
  volume       = {15},
  year         = {2019},
}