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Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease

Brattås, Per Ludvik LU ; Hersbach, Bob A. ; Madsen, Sofia LU ; Petri, Rebecca LU ; Jakobsson, Johan LU orcid and Pircs, Karolina LU orcid (2021) In Autophagy 17(6). p.1316-1329
Abstract

Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator... (More)

Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adeno-associated viral vectors, autophagy, BECN1/beclin-1, Huntington disease, macroautophagy, neurodegeneration, TFEB
in
Autophagy
volume
17
issue
6
pages
14 pages
publisher
Landes Bioscience
external identifiers
  • pmid:32374203
  • scopus:85084324970
ISSN
1554-8627
DOI
10.1080/15548627.2020.1760014
language
English
LU publication?
yes
id
35d492da-97b2-42f8-8df9-6ab243658ede
date added to LUP
2020-06-10 16:25:39
date last changed
2022-09-24 06:49:00
@article{35d492da-97b2-42f8-8df9-6ab243658ede,
  abstract     = {{<p>Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.</p>}},
  author       = {{Brattås, Per Ludvik and Hersbach, Bob A. and Madsen, Sofia and Petri, Rebecca and Jakobsson, Johan and Pircs, Karolina}},
  issn         = {{1554-8627}},
  keywords     = {{Adeno-associated viral vectors; autophagy; BECN1/beclin-1; Huntington disease; macroautophagy; neurodegeneration; TFEB}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1316--1329}},
  publisher    = {{Landes Bioscience}},
  series       = {{Autophagy}},
  title        = {{Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease}},
  url          = {{http://dx.doi.org/10.1080/15548627.2020.1760014}},
  doi          = {{10.1080/15548627.2020.1760014}},
  volume       = {{17}},
  year         = {{2021}},
}