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

Youren Tong, Hiroo Yamaguchi, Emilie Giaime, Scott Boyle, Raphael Kopan, Raymond J. Kelleher, Jie Shen

    Research output: Contribution to journalArticle

    300 Citations (Scopus)

    Abstract

    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 aswell 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.

    Original languageEnglish
    Pages (from-to)9879-9884
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number21
    DOIs
    Publication statusPublished - May 25 2010

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    Synucleins
    Leucine
    Proteolysis
    Cell Death
    Phosphotransferases
    Parkinson Disease
    Ubiquitinated Proteins
    Corpus Striatum
    Lipofuscin
    Mutation
    Monomeric GTP-Binding Proteins
    Dopaminergic Neurons
    Autophagy
    Germ Cells
    Dopamine
    Proteins
    Homeostasis

    All Science Journal Classification (ASJC) codes

    • General

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    Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice. / Tong, Youren; Yamaguchi, Hiroo; Giaime, Emilie; Boyle, Scott; Kopan, Raphael; Kelleher, Raymond J.; Shen, Jie.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 21, 25.05.2010, p. 9879-9884.

    Research output: Contribution to journalArticle

    Tong, Youren ; Yamaguchi, Hiroo ; Giaime, Emilie ; Boyle, Scott ; Kopan, Raphael ; Kelleher, Raymond J. ; Shen, Jie. / Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 21. pp. 9879-9884.
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