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Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway
BACKGROUND: Dominantly inherited missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, but its normal physiological function remains unclear. We previously reported that loss of LRRK2 causes impairment of protein degradation pathway...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296570/ https://www.ncbi.nlm.nih.gov/pubmed/22230652 http://dx.doi.org/10.1186/1750-1326-7-2 |
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author | Tong, Youren Giaime, Emilie Yamaguchi, Hiroo Ichimura, Takaharu Liu, Yumin Si, Huiqing Cai, Huaibin Bonventre, Joseph V Shen, Jie |
author_facet | Tong, Youren Giaime, Emilie Yamaguchi, Hiroo Ichimura, Takaharu Liu, Yumin Si, Huiqing Cai, Huaibin Bonventre, Joseph V Shen, Jie |
author_sort | Tong, Youren |
collection | PubMed |
description | BACKGROUND: Dominantly inherited missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, but its normal physiological function remains unclear. We previously reported that loss of LRRK2 causes impairment of protein degradation pathways as well as increases of apoptotic cell death and inflammatory responses in the kidney of aged mice. RESULTS: Our analysis of LRRK2-/- kidneys at multiple ages, such as 1, 4, 7, and 20 months, revealed unique age-dependent development of a variety of molecular, cellular, and ultrastructural changes. Gross morphological abnormalities of the kidney, including altered size, weight, texture, and color, are evident in LRRK2-/- mice at 3-4 months of age, along with increased accumulation of autofluorescent granules in proximal renal tubules. The ratio of kidney/body weight in LRRK2-/- mice is increased at 1, 4, and 7 months of age (~10% at 1 month, and ~20% at 4 and 7 months), whereas the ratio is drastically decreased at 20 months of age (~50%). While kidney filtration function evaluated by levels of blood urea nitrogen and serum creatinine is not significantly affected in LRRK2-/- mice at 12-14 months of age, expression of kidney injury molecule-1, a sensitive and specific biomarker for epithelial cell injury of proximal renal tubules, is up-regulated (~10-fold). Surprisingly, loss of LRRK2 causes age-dependent bi-phasic alterations of the autophagic activity in LRRK2-/- kidneys, which is unchanged at 1 month of age, enhanced at 7 months but reduced at 20 months, as evidenced by corresponding changes in the levels of LC3-I/II, a reliable autophagy marker, and p62, an autophagy substrate. Levels of α-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in LRRK2-/- kidneys at 7 months of age but increased at 20 months. Interestingly, the age-dependent bi-phasic alterations in autophagic activity in LRRK2-/- kidneys is accompanied by increased levels of lysosomal proteins and proteases at 1, 7, and 20 months of age as well as progressive accumulation of autolysosomes and lipofuscin granules at 4, 7-10, and 20 months of age. CONCLUSIONS: LRRK2 is important for the dynamic regulation of autophagy function in vivo. |
format | Online Article Text |
id | pubmed-3296570 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-32965702012-03-08 Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway Tong, Youren Giaime, Emilie Yamaguchi, Hiroo Ichimura, Takaharu Liu, Yumin Si, Huiqing Cai, Huaibin Bonventre, Joseph V Shen, Jie Mol Neurodegener Research Article BACKGROUND: Dominantly inherited missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, but its normal physiological function remains unclear. We previously reported that loss of LRRK2 causes impairment of protein degradation pathways as well as increases of apoptotic cell death and inflammatory responses in the kidney of aged mice. RESULTS: Our analysis of LRRK2-/- kidneys at multiple ages, such as 1, 4, 7, and 20 months, revealed unique age-dependent development of a variety of molecular, cellular, and ultrastructural changes. Gross morphological abnormalities of the kidney, including altered size, weight, texture, and color, are evident in LRRK2-/- mice at 3-4 months of age, along with increased accumulation of autofluorescent granules in proximal renal tubules. The ratio of kidney/body weight in LRRK2-/- mice is increased at 1, 4, and 7 months of age (~10% at 1 month, and ~20% at 4 and 7 months), whereas the ratio is drastically decreased at 20 months of age (~50%). While kidney filtration function evaluated by levels of blood urea nitrogen and serum creatinine is not significantly affected in LRRK2-/- mice at 12-14 months of age, expression of kidney injury molecule-1, a sensitive and specific biomarker for epithelial cell injury of proximal renal tubules, is up-regulated (~10-fold). Surprisingly, loss of LRRK2 causes age-dependent bi-phasic alterations of the autophagic activity in LRRK2-/- kidneys, which is unchanged at 1 month of age, enhanced at 7 months but reduced at 20 months, as evidenced by corresponding changes in the levels of LC3-I/II, a reliable autophagy marker, and p62, an autophagy substrate. Levels of α-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in LRRK2-/- kidneys at 7 months of age but increased at 20 months. Interestingly, the age-dependent bi-phasic alterations in autophagic activity in LRRK2-/- kidneys is accompanied by increased levels of lysosomal proteins and proteases at 1, 7, and 20 months of age as well as progressive accumulation of autolysosomes and lipofuscin granules at 4, 7-10, and 20 months of age. CONCLUSIONS: LRRK2 is important for the dynamic regulation of autophagy function in vivo. BioMed Central 2012-01-09 /pmc/articles/PMC3296570/ /pubmed/22230652 http://dx.doi.org/10.1186/1750-1326-7-2 Text en Copyright ©2012 Tong et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Tong, Youren Giaime, Emilie Yamaguchi, Hiroo Ichimura, Takaharu Liu, Yumin Si, Huiqing Cai, Huaibin Bonventre, Joseph V Shen, Jie Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway |
title | Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway |
title_full | Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway |
title_fullStr | Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway |
title_full_unstemmed | Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway |
title_short | Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway |
title_sort | loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296570/ https://www.ncbi.nlm.nih.gov/pubmed/22230652 http://dx.doi.org/10.1186/1750-1326-7-2 |
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