Cargando…

Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo

The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D (CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis (NCL) and is important in removi...

Descripción completa

Detalles Bibliográficos
Autores principales: Ouyang, Xiaosen, Wani, Willayat Y., Benavides, Gloria A., Redmann, Matthew J., Vo, Hai, van Groen, Thomas, Darley-Usmar, Victor M., Zhang, Jianhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547960/
https://www.ncbi.nlm.nih.gov/pubmed/37799377
http://dx.doi.org/10.1016/j.apsb.2023.07.015
_version_ 1785115171314728960
author Ouyang, Xiaosen
Wani, Willayat Y.
Benavides, Gloria A.
Redmann, Matthew J.
Vo, Hai
van Groen, Thomas
Darley-Usmar, Victor M.
Zhang, Jianhua
author_facet Ouyang, Xiaosen
Wani, Willayat Y.
Benavides, Gloria A.
Redmann, Matthew J.
Vo, Hai
van Groen, Thomas
Darley-Usmar, Victor M.
Zhang, Jianhua
author_sort Ouyang, Xiaosen
collection PubMed
description The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D (CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis (NCL) and is important in removing toxic protein aggregates. Prior studies demonstrated that CTSD germ-line knockout-CtsdKO (CDKO) resulted in accumulation of protein aggregates, decreased proteasomal activities, and postnatal lethality on Day 26 ± 1. Overexpression of wildtype CTSD, but not cathepsin B, L or mutant CTSD, decreased α-synuclein toxicity in worms and mammalian cells. In this study we generated a mouse line expressing human CTSD with a floxed STOP cassette between the ubiquitous CAG promoter and the cDNA. After crossing with Nestin-cre, the STOP cassette is deleted in NESTIN + cells to allow CTSD overexpression-CTSDtg (CDtg). The CDtg mice exhibited normal behavior and similar sensitivity to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurodegeneration. By breeding CDtg mice with CDKO mice, we found that over-expression of CTSD extended the lifespan of the CDKO mice, partially rescued proteasomal deficits and the accumulation of Aβ42 in the CDKO. This new transgenic mouse provides supports for the key role of CTSD in protecting against proteotoxicity and offers a new model to study the role of CTSD enhancement in vivo.
format Online
Article
Text
id pubmed-10547960
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-105479602023-10-05 Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo Ouyang, Xiaosen Wani, Willayat Y. Benavides, Gloria A. Redmann, Matthew J. Vo, Hai van Groen, Thomas Darley-Usmar, Victor M. Zhang, Jianhua Acta Pharm Sin B Original Article The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D (CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis (NCL) and is important in removing toxic protein aggregates. Prior studies demonstrated that CTSD germ-line knockout-CtsdKO (CDKO) resulted in accumulation of protein aggregates, decreased proteasomal activities, and postnatal lethality on Day 26 ± 1. Overexpression of wildtype CTSD, but not cathepsin B, L or mutant CTSD, decreased α-synuclein toxicity in worms and mammalian cells. In this study we generated a mouse line expressing human CTSD with a floxed STOP cassette between the ubiquitous CAG promoter and the cDNA. After crossing with Nestin-cre, the STOP cassette is deleted in NESTIN + cells to allow CTSD overexpression-CTSDtg (CDtg). The CDtg mice exhibited normal behavior and similar sensitivity to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurodegeneration. By breeding CDtg mice with CDKO mice, we found that over-expression of CTSD extended the lifespan of the CDKO mice, partially rescued proteasomal deficits and the accumulation of Aβ42 in the CDKO. This new transgenic mouse provides supports for the key role of CTSD in protecting against proteotoxicity and offers a new model to study the role of CTSD enhancement in vivo. Elsevier 2023-10 2023-07-20 /pmc/articles/PMC10547960/ /pubmed/37799377 http://dx.doi.org/10.1016/j.apsb.2023.07.015 Text en © 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Ouyang, Xiaosen
Wani, Willayat Y.
Benavides, Gloria A.
Redmann, Matthew J.
Vo, Hai
van Groen, Thomas
Darley-Usmar, Victor M.
Zhang, Jianhua
Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo
title Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo
title_full Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo
title_fullStr Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo
title_full_unstemmed Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo
title_short Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo
title_sort cathepsin d overexpression in the nervous system rescues lethality and aβ42 accumulation of cathepsin d systemic knockout in vivo
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547960/
https://www.ncbi.nlm.nih.gov/pubmed/37799377
http://dx.doi.org/10.1016/j.apsb.2023.07.015
work_keys_str_mv AT ouyangxiaosen cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo
AT waniwillayaty cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo
AT benavidesgloriaa cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo
AT redmannmatthewj cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo
AT vohai cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo
AT vangroenthomas cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo
AT darleyusmarvictorm cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo
AT zhangjianhua cathepsindoverexpressioninthenervoussystemrescueslethalityandab42accumulationofcathepsindsystemicknockoutinvivo