Loss of Leucine-rich Repeat Kinase 2 Causes Age-dependent Bi-phasic Alterations of the Autophagy Pathway

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Loss of Leucine-rich Repeat Kinase 2 Causes Age-dependent Bi-phasic Alterations of the Autophagy Pathway

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dc.contributor.author Tong, Youren
dc.contributor.author Giaime, Emilie
dc.contributor.author Yamaguchi, Hiroo
dc.contributor.author Ichimura, Takaharu
dc.contributor.author Liu, Yumin
dc.contributor.author Si, Huiqing
dc.contributor.author Cai, Huaibin
dc.contributor.author Bonventre, Joseph Vincent
dc.contributor.author Shen, Jie
dc.date.accessioned 2012-09-25T14:03:41Z
dc.date.issued 2012
dc.identifier.citation Tong, Youren, Emilie Giaime, Hiroo Yamaguchi, Takaharu Ichimura, Yumin Liu, Huiqing Si, Huaibin Cai, Joseph V. Bonventre, and Jie Shen. 2012. Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Molecular Neurodegeneration 7:2. en_US
dc.identifier.issn 1750-1326 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:9637982
dc.description.abstract 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 (\( \sim 10 \%\) at 1 month, and (\( \sim20\%\) at 4 and 7 months), whereas the ratio is drastically decreased at 20 months of age (\( \sim50\%\)). 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 (\( \sim 10-fold\)). 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. en_US
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.relation.isversionof doi:10.1186/1750-1326-7-2 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296570/pdf/ en_US
dash.license LAA
dc.subject LRRK2 en_US
dc.subject Parkinson’s disease en_US
dc.subject knockout en_US
dc.subject LC3 en_US
dc.subject p62 en_US
dc.subject lysosomal proteins en_US
dc.subject cathepsins en_US
dc.subject lipofuscin en_US
dc.title Loss of Leucine-rich Repeat Kinase 2 Causes Age-dependent Bi-phasic Alterations of the Autophagy Pathway en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Molecular Neurodegeneration en_US
dash.depositing.author Tong, Youren
dc.date.available 2012-09-25T14:03:41Z

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