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Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1
HTRA2, a serine protease in the intermembrane space, has important functions in mitochondrial stress signaling while its abnormal activity may contribute to the development of Parkinson’s disease. Mice with a missense or null mutation of Htra2 fail to thrive, suffer striatal neuronal loss, and a par...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274161/ https://www.ncbi.nlm.nih.gov/pubmed/25531304 http://dx.doi.org/10.1371/journal.pone.0115789 |
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author | Patterson, Victoria L. Zullo, Alfred J. Koenig, Claire Stoessel, Sean Jo, Hakryul Liu, Xinran Han, Jinah Choi, Murim DeWan, Andrew T. Thomas, Jean-Leon Kuan, Chia-Yi Hoh, Josephine |
author_facet | Patterson, Victoria L. Zullo, Alfred J. Koenig, Claire Stoessel, Sean Jo, Hakryul Liu, Xinran Han, Jinah Choi, Murim DeWan, Andrew T. Thomas, Jean-Leon Kuan, Chia-Yi Hoh, Josephine |
author_sort | Patterson, Victoria L. |
collection | PubMed |
description | HTRA2, a serine protease in the intermembrane space, has important functions in mitochondrial stress signaling while its abnormal activity may contribute to the development of Parkinson’s disease. Mice with a missense or null mutation of Htra2 fail to thrive, suffer striatal neuronal loss, and a parkinsonian phenotype that leads to death at 30–40 days of age. While informative, these mouse models cannot separate neural contributions from systemic effects due to the complex phenotypes of HTRA2 deficiency. Hence, we developed mice carrying a Htra2-floxed allele to query the consequences of tissue-specific HTRA2 deficiency. We found that mice with neural-specific deletion of Htra2 exhibited atrophy of the thymus and spleen, cessation to gain weight past postnatal (P) day 18, neurological symptoms including ataxia and complete penetrance of premature death by P40. Histologically, increased apoptosis was detected in the cerebellum, and to a lesser degree in the striatum and the entorhinal cortex, from P25. Even earlier at P20, mitochondria in the cerebella already exhibited abnormal morphology, including swelling, vesiculation, and fragmentation of the cristae. Furthermore, the onset of these structural anomalies was accompanied by defective processing of OPA1, a key molecule for mitochondrial fusion and cristae remodeling, leading to depletion of the L-isoform. Together, these findings suggest that HTRA2 is essential for maintenance of the mitochondrial integrity in neurons. Without functional HTRA2, a lifespan as short as 40 days accumulates a large quantity of dysfunctional mitochondria that contributes to the demise of mutant mice. |
format | Online Article Text |
id | pubmed-4274161 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-42741612014-12-31 Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 Patterson, Victoria L. Zullo, Alfred J. Koenig, Claire Stoessel, Sean Jo, Hakryul Liu, Xinran Han, Jinah Choi, Murim DeWan, Andrew T. Thomas, Jean-Leon Kuan, Chia-Yi Hoh, Josephine PLoS One Research Article HTRA2, a serine protease in the intermembrane space, has important functions in mitochondrial stress signaling while its abnormal activity may contribute to the development of Parkinson’s disease. Mice with a missense or null mutation of Htra2 fail to thrive, suffer striatal neuronal loss, and a parkinsonian phenotype that leads to death at 30–40 days of age. While informative, these mouse models cannot separate neural contributions from systemic effects due to the complex phenotypes of HTRA2 deficiency. Hence, we developed mice carrying a Htra2-floxed allele to query the consequences of tissue-specific HTRA2 deficiency. We found that mice with neural-specific deletion of Htra2 exhibited atrophy of the thymus and spleen, cessation to gain weight past postnatal (P) day 18, neurological symptoms including ataxia and complete penetrance of premature death by P40. Histologically, increased apoptosis was detected in the cerebellum, and to a lesser degree in the striatum and the entorhinal cortex, from P25. Even earlier at P20, mitochondria in the cerebella already exhibited abnormal morphology, including swelling, vesiculation, and fragmentation of the cristae. Furthermore, the onset of these structural anomalies was accompanied by defective processing of OPA1, a key molecule for mitochondrial fusion and cristae remodeling, leading to depletion of the L-isoform. Together, these findings suggest that HTRA2 is essential for maintenance of the mitochondrial integrity in neurons. Without functional HTRA2, a lifespan as short as 40 days accumulates a large quantity of dysfunctional mitochondria that contributes to the demise of mutant mice. Public Library of Science 2014-12-22 /pmc/articles/PMC4274161/ /pubmed/25531304 http://dx.doi.org/10.1371/journal.pone.0115789 Text en © 2014 Patterson et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Patterson, Victoria L. Zullo, Alfred J. Koenig, Claire Stoessel, Sean Jo, Hakryul Liu, Xinran Han, Jinah Choi, Murim DeWan, Andrew T. Thomas, Jean-Leon Kuan, Chia-Yi Hoh, Josephine Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 |
title | Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 |
title_full | Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 |
title_fullStr | Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 |
title_full_unstemmed | Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 |
title_short | Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 |
title_sort | neural-specific deletion of htra2 causes cerebellar neurodegeneration and defective processing of mitochondrial opa1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274161/ https://www.ncbi.nlm.nih.gov/pubmed/25531304 http://dx.doi.org/10.1371/journal.pone.0115789 |
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