---
_id: '9363'
abstract:
- lang: eng
  text: 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.
acknowledgement: We thank R. Cagan, A. Whitworth and J. Nagpal for fly lines and advice,
  S. Herlitze for provision of a tissue culture illuminator, and Verian Bader for
  help with statistical analysis.
article_processing_charge: No
author:
- first_name: Álvaro
  full_name: Inglés Prieto, Álvaro
  id: 2A9DB292-F248-11E8-B48F-1D18A9856A87
  last_name: Inglés Prieto
  orcid: 0000-0002-5409-8571
- first_name: Nikolas
  full_name: Furthmann, Nikolas
  last_name: Furthmann
- first_name: Samuel H.
  full_name: Crossman, Samuel H.
  last_name: Crossman
- first_name: Alexandra Madelaine
  full_name: Tichy, Alexandra Madelaine
  last_name: Tichy
- first_name: Nina
  full_name: Hoyer, Nina
  last_name: Hoyer
- first_name: Meike
  full_name: Petersen, Meike
  last_name: Petersen
- first_name: Vanessa
  full_name: Zheden, Vanessa
  id: 39C5A68A-F248-11E8-B48F-1D18A9856A87
  last_name: Zheden
- first_name: Julia
  full_name: Bicher, Julia
  id: 3CCBB46E-F248-11E8-B48F-1D18A9856A87
  last_name: Bicher
- first_name: Eva
  full_name: Gschaider-Reichhart, Eva
  id: 3FEE232A-F248-11E8-B48F-1D18A9856A87
  last_name: Gschaider-Reichhart
  orcid: 0000-0002-7218-7738
- first_name: Attila
  full_name: György, Attila
  id: 3BCEDBE0-F248-11E8-B48F-1D18A9856A87
  last_name: György
  orcid: 0000-0002-1819-198X
- first_name: Daria E
  full_name: Siekhaus, Daria E
  id: 3D224B9E-F248-11E8-B48F-1D18A9856A87
  last_name: Siekhaus
  orcid: 0000-0001-8323-8353
- first_name: Peter
  full_name: Soba, Peter
  last_name: Soba
- first_name: Konstanze F.
  full_name: Winklhofer, Konstanze F.
  last_name: Winklhofer
- first_name: Harald L
  full_name: Janovjak, Harald L
  id: 33BA6C30-F248-11E8-B48F-1D18A9856A87
  last_name: Janovjak
  orcid: 0000-0002-8023-9315
citation:
  ama: Inglés Prieto Á, Furthmann N, Crossman SH, et al. Optogenetic delivery of trophic
    signals in a genetic model of Parkinson’s disease. <i>PLoS genetics</i>. 2021;17(4):e1009479.
    doi:<a href="https://doi.org/10.1371/journal.pgen.1009479">10.1371/journal.pgen.1009479</a>
  apa: Inglés Prieto, Á., Furthmann, N., Crossman, S. H., Tichy, A. M., Hoyer, N.,
    Petersen, M., … Janovjak, H. L. (2021). Optogenetic delivery of trophic signals
    in a genetic model of Parkinson’s disease. <i>PLoS Genetics</i>. Public Library
    of Science. <a href="https://doi.org/10.1371/journal.pgen.1009479">https://doi.org/10.1371/journal.pgen.1009479</a>
  chicago: Inglés Prieto, Álvaro, Nikolas Furthmann, Samuel H. Crossman, Alexandra
    Madelaine Tichy, Nina Hoyer, Meike Petersen, Vanessa Zheden, et al. “Optogenetic
    Delivery of Trophic Signals in a Genetic Model of Parkinson’s Disease.” <i>PLoS
    Genetics</i>. Public Library of Science, 2021. <a href="https://doi.org/10.1371/journal.pgen.1009479">https://doi.org/10.1371/journal.pgen.1009479</a>.
  ieee: Á. Inglés Prieto <i>et al.</i>, “Optogenetic delivery of trophic signals in
    a genetic model of Parkinson’s disease,” <i>PLoS genetics</i>, vol. 17, no. 4.
    Public Library of Science, p. e1009479, 2021.
  ista: Inglés Prieto Á, Furthmann N, Crossman SH, Tichy AM, Hoyer N, Petersen M,
    Zheden V, Bicher J, Gschaider-Reichhart E, György A, Siekhaus DE, Soba P, Winklhofer
    KF, Janovjak HL. 2021. Optogenetic delivery of trophic signals in a genetic model
    of Parkinson’s disease. PLoS genetics. 17(4), e1009479.
  mla: Inglés Prieto, Álvaro, et al. “Optogenetic Delivery of Trophic Signals in a
    Genetic Model of Parkinson’s Disease.” <i>PLoS Genetics</i>, vol. 17, no. 4, Public
    Library of Science, 2021, p. e1009479, doi:<a href="https://doi.org/10.1371/journal.pgen.1009479">10.1371/journal.pgen.1009479</a>.
  short: Á. Inglés Prieto, N. Furthmann, S.H. Crossman, A.M. Tichy, N. Hoyer, M. Petersen,
    V. Zheden, J. Bicher, E. Gschaider-Reichhart, A. György, D.E. Siekhaus, P. Soba,
    K.F. Winklhofer, H.L. Janovjak, PLoS Genetics 17 (2021) e1009479.
date_created: 2021-05-02T22:01:29Z
date_published: 2021-04-01T00:00:00Z
date_updated: 2023-08-08T13:17:47Z
day: '01'
ddc:
- '570'
department:
- _id: EM-Fac
- _id: LoSw
- _id: DaSi
doi: 10.1371/journal.pgen.1009479
external_id:
  isi:
  - '000640606700001'
file:
- access_level: open_access
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  date_created: 2021-05-04T09:05:27Z
  date_updated: 2021-05-04T09:05:27Z
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  file_size: 3072764
  relation: main_file
  success: 1
file_date_updated: 2021-05-04T09:05:27Z
has_accepted_license: '1'
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isi: 1
issue: '4'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '04'
oa: 1
oa_version: Published Version
page: e1009479
publication: PLoS genetics
publication_identifier:
  eissn:
  - '15537404'
publication_status: published
publisher: Public Library of Science
quality_controlled: '1'
scopus_import: '1'
status: public
title: Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 17
year: '2021'
...
---
_id: '6419'
abstract:
- lang: eng
  text: 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.
article_number: e1008079
article_processing_charge: No
author:
- first_name: Victoria
  full_name: Pokusaeva, Victoria
  id: 3184041C-F248-11E8-B48F-1D18A9856A87
  last_name: Pokusaeva
  orcid: 0000-0001-7660-444X
- first_name: Dinara R.
  full_name: Usmanova, Dinara R.
  last_name: Usmanova
- first_name: Ekaterina V.
  full_name: Putintseva, Ekaterina V.
  last_name: Putintseva
- first_name: Lorena
  full_name: Espinar, Lorena
  last_name: Espinar
- first_name: Karen
  full_name: Sarkisyan, Karen
  id: 39A7BF80-F248-11E8-B48F-1D18A9856A87
  last_name: Sarkisyan
  orcid: 0000-0002-5375-6341
- first_name: Alexander S.
  full_name: Mishin, Alexander S.
  last_name: Mishin
- first_name: Natalya S.
  full_name: Bogatyreva, Natalya S.
  last_name: Bogatyreva
- first_name: Dmitry
  full_name: Ivankov, Dmitry
  id: 49FF1036-F248-11E8-B48F-1D18A9856A87
  last_name: Ivankov
- first_name: Arseniy
  full_name: Akopyan, Arseniy
  id: 430D2C90-F248-11E8-B48F-1D18A9856A87
  last_name: Akopyan
  orcid: 0000-0002-2548-617X
- first_name: Sergey
  full_name: Avvakumov, Sergey
  id: 3827DAC8-F248-11E8-B48F-1D18A9856A87
  last_name: Avvakumov
- first_name: Inna S.
  full_name: Povolotskaya, Inna S.
  last_name: Povolotskaya
- first_name: Guillaume J.
  full_name: Filion, Guillaume J.
  last_name: Filion
- first_name: Lucas B.
  full_name: Carey, Lucas B.
  last_name: Carey
- first_name: Fyodor
  full_name: Kondrashov, Fyodor
  id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
  last_name: Kondrashov
  orcid: 0000-0001-8243-4694
citation:
  ama: Pokusaeva V, Usmanova DR, Putintseva EV, et al. An experimental assay of the
    interactions of amino acids from orthologous sequences shaping a complex fitness
    landscape. <i>PLoS Genetics</i>. 2019;15(4). doi:<a href="https://doi.org/10.1371/journal.pgen.1008079">10.1371/journal.pgen.1008079</a>
  apa: Pokusaeva, V., Usmanova, D. R., Putintseva, E. V., Espinar, L., Sarkisyan,
    K., Mishin, A. S., … Kondrashov, F. (2019). An experimental assay of the interactions
    of amino acids from orthologous sequences shaping a complex fitness landscape.
    <i>PLoS Genetics</i>. Public Library of Science. <a href="https://doi.org/10.1371/journal.pgen.1008079">https://doi.org/10.1371/journal.pgen.1008079</a>
  chicago: Pokusaeva, Victoria, Dinara R. Usmanova, Ekaterina V. Putintseva, Lorena
    Espinar, Karen Sarkisyan, Alexander S. Mishin, Natalya S. Bogatyreva, et al. “An
    Experimental Assay of the Interactions of Amino Acids from Orthologous Sequences
    Shaping a Complex Fitness Landscape.” <i>PLoS Genetics</i>. Public Library of
    Science, 2019. <a href="https://doi.org/10.1371/journal.pgen.1008079">https://doi.org/10.1371/journal.pgen.1008079</a>.
  ieee: V. Pokusaeva <i>et al.</i>, “An experimental assay of the interactions of
    amino acids from orthologous sequences shaping a complex fitness landscape,” <i>PLoS
    Genetics</i>, vol. 15, no. 4. Public Library of Science, 2019.
  ista: Pokusaeva V, Usmanova DR, Putintseva EV, Espinar L, Sarkisyan K, Mishin AS,
    Bogatyreva NS, Ivankov D, Akopyan A, Avvakumov S, Povolotskaya IS, Filion GJ,
    Carey LB, Kondrashov F. 2019. An experimental assay of the interactions of amino
    acids from orthologous sequences shaping a complex fitness landscape. PLoS Genetics.
    15(4), e1008079.
  mla: Pokusaeva, Victoria, et al. “An Experimental Assay of the Interactions of Amino
    Acids from Orthologous Sequences Shaping a Complex Fitness Landscape.” <i>PLoS
    Genetics</i>, vol. 15, no. 4, e1008079, Public Library of Science, 2019, doi:<a
    href="https://doi.org/10.1371/journal.pgen.1008079">10.1371/journal.pgen.1008079</a>.
  short: V. Pokusaeva, D.R. Usmanova, E.V. Putintseva, L. Espinar, K. Sarkisyan, A.S.
    Mishin, N.S. Bogatyreva, D. Ivankov, A. Akopyan, S. Avvakumov, I.S. Povolotskaya,
    G.J. Filion, L.B. Carey, F. Kondrashov, PLoS Genetics 15 (2019).
date_created: 2019-05-13T07:58:38Z
date_published: 2019-04-10T00:00:00Z
date_updated: 2023-08-25T10:30:37Z
day: '10'
ddc:
- '570'
department:
- _id: FyKo
doi: 10.1371/journal.pgen.1008079
ec_funded: 1
external_id:
  isi:
  - '000466866000029'
file:
- access_level: open_access
  checksum: cf3889c8a8a16053dacf9c3776cbe217
  content_type: application/pdf
  creator: dernst
  date_created: 2019-05-14T08:26:08Z
  date_updated: 2020-07-14T12:47:30Z
  file_id: '6445'
  file_name: 2019_PLOSGenetics_Pokusaeva.pdf
  file_size: 3726017
  relation: main_file
file_date_updated: 2020-07-14T12:47:30Z
has_accepted_license: '1'
intvolume: '        15'
isi: 1
issue: '4'
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
project:
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '665385'
  name: International IST Doctoral Program
publication: PLoS Genetics
publication_identifier:
  eissn:
  - '15537404'
publication_status: published
publisher: Public Library of Science
quality_controlled: '1'
related_material:
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    status: public
  - id: '9790'
    relation: research_data
    status: public
  - id: '9797'
    relation: research_data
    status: public
scopus_import: '1'
status: public
title: An experimental assay of the interactions of amino acids from orthologous sequences
  shaping a complex fitness landscape
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 15
year: '2019'
...