Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two in...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2010-05, Vol.107 (21), p.9879-9884
Main Authors: Tong, Youren, Yamaguchi, Hiroo, Giaime, Emilie, Boyle, Scott, Kopan, Raphael, Kelleher, Raymond J. III, Shen, Jie
Format: Article
Language:English
Subjects:
Aggregation
Aging
Alleles
alpha-Synuclein - metabolism
Animals
Antibodies
Apoptosis
Autophagy
Biological Sciences
Cell death
Dopamine - metabolism
Genetic mutation
Homeostasis
Kidney Diseases - genetics
Kidney Diseases - metabolism
Kidney Diseases - pathology
Kidneys
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Lysosomes - metabolism
Messenger RNA
Mice
Mice, Knockout
Neurons
Oxidation-Reduction
Parkinson disease
Protein Serine-Threonine Kinases - deficiency
Protein Serine-Threonine Kinases - metabolism
Ubiquitination
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Summary:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2⁻/⁻ mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2⁻/⁻ kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1004676107