R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Youren Tong, Antonio Pisani, Giuseppina Martella, Maha Karouani, hiroo yamaguchi, Emmanuel N. Pothos, Jie Shen

    Research output: Contribution to journalArticle

    184 Citations (Scopus)

    Abstract

    Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease (PD). The importance of the R1441 residue in the pathogenesis is highlighted by the identification of three distinct missense mutations. To investigate the pathogenic mechanism underlying LRRK2 dysfunction, we generated a knockin (KI) mouse in which the R1441C mutation is expressed under the control of the endogenous regulatory elements. Homozygous R1441C KI mice appear grossly normal and exhibit no dopaminergic (DA) neurodegeneration or alterations in steady-state levels of striatal dopamine up to 2 years of age. However, these KI mice show reductions in amphetamine (AMPH)-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells. The introduction of the R1441C mutation also impairs dopamine D2 receptor function, as suggested by decreased responses of KI mice in locomotor activity to the inhibitory effect of a D2 receptor agonist, quinpirole. Furthermore, the firing of nigral neurons in R1441C KI mice show reduced sensitivity to suppression induced by quinpirole, dopamine, or AMPH. Together, our data suggest that the R1441C mutation in LRRK2 impairs stimulated dopamine neurotransmission and D2 receptor function, which may represent pathogenic precursors preceding dopaminergic degeneration in PD brains.

    Original languageEnglish
    Pages (from-to)14622-14627
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume106
    Issue number34
    DOIs
    Publication statusPublished - Aug 25 2009

    Fingerprint

    Leucine
    Synaptic Transmission
    Phosphotransferases
    Mutation
    Quinpirole
    Dopamine D2 Receptors
    Amphetamine
    Locomotion
    Parkinson Disease
    Dopamine
    Corpus Striatum
    Chromaffin Cells
    Substantia Nigra
    Missense Mutation
    Catecholamines
    Cultured Cells
    Neurons
    Brain

    All Science Journal Classification (ASJC) codes

    • General

    Cite this

    R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. / Tong, Youren; Pisani, Antonio; Martella, Giuseppina; Karouani, Maha; yamaguchi, hiroo; Pothos, Emmanuel N.; Shen, Jie.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 34, 25.08.2009, p. 14622-14627.

    Research output: Contribution to journalArticle

    Tong, Y, Pisani, A, Martella, G, Karouani, M, yamaguchi, H, Pothos, EN & Shen, J 2009, 'R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 34, pp. 14622-14627. https://doi.org/10.1073/pnas.0906334106
    Tong, Youren ; Pisani, Antonio ; Martella, Giuseppina ; Karouani, Maha ; yamaguchi, hiroo ; Pothos, Emmanuel N. ; Shen, Jie. / R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 34. pp. 14622-14627.
    @article{1076b2d3228f4dc9a7c4e0b64a86c80a,
    title = "R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice",
    abstract = "Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease (PD). The importance of the R1441 residue in the pathogenesis is highlighted by the identification of three distinct missense mutations. To investigate the pathogenic mechanism underlying LRRK2 dysfunction, we generated a knockin (KI) mouse in which the R1441C mutation is expressed under the control of the endogenous regulatory elements. Homozygous R1441C KI mice appear grossly normal and exhibit no dopaminergic (DA) neurodegeneration or alterations in steady-state levels of striatal dopamine up to 2 years of age. However, these KI mice show reductions in amphetamine (AMPH)-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells. The introduction of the R1441C mutation also impairs dopamine D2 receptor function, as suggested by decreased responses of KI mice in locomotor activity to the inhibitory effect of a D2 receptor agonist, quinpirole. Furthermore, the firing of nigral neurons in R1441C KI mice show reduced sensitivity to suppression induced by quinpirole, dopamine, or AMPH. Together, our data suggest that the R1441C mutation in LRRK2 impairs stimulated dopamine neurotransmission and D2 receptor function, which may represent pathogenic precursors preceding dopaminergic degeneration in PD brains.",
    author = "Youren Tong and Antonio Pisani and Giuseppina Martella and Maha Karouani and hiroo yamaguchi and Pothos, {Emmanuel N.} and Jie Shen",
    year = "2009",
    month = "8",
    day = "25",
    doi = "10.1073/pnas.0906334106",
    language = "English",
    volume = "106",
    pages = "14622--14627",
    journal = "Proceedings of the National Academy of Sciences of the United States of America",
    issn = "0027-8424",
    number = "34",

    }

    TY - JOUR

    T1 - R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

    AU - Tong, Youren

    AU - Pisani, Antonio

    AU - Martella, Giuseppina

    AU - Karouani, Maha

    AU - yamaguchi, hiroo

    AU - Pothos, Emmanuel N.

    AU - Shen, Jie

    PY - 2009/8/25

    Y1 - 2009/8/25

    N2 - Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease (PD). The importance of the R1441 residue in the pathogenesis is highlighted by the identification of three distinct missense mutations. To investigate the pathogenic mechanism underlying LRRK2 dysfunction, we generated a knockin (KI) mouse in which the R1441C mutation is expressed under the control of the endogenous regulatory elements. Homozygous R1441C KI mice appear grossly normal and exhibit no dopaminergic (DA) neurodegeneration or alterations in steady-state levels of striatal dopamine up to 2 years of age. However, these KI mice show reductions in amphetamine (AMPH)-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells. The introduction of the R1441C mutation also impairs dopamine D2 receptor function, as suggested by decreased responses of KI mice in locomotor activity to the inhibitory effect of a D2 receptor agonist, quinpirole. Furthermore, the firing of nigral neurons in R1441C KI mice show reduced sensitivity to suppression induced by quinpirole, dopamine, or AMPH. Together, our data suggest that the R1441C mutation in LRRK2 impairs stimulated dopamine neurotransmission and D2 receptor function, which may represent pathogenic precursors preceding dopaminergic degeneration in PD brains.

    AB - Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease (PD). The importance of the R1441 residue in the pathogenesis is highlighted by the identification of three distinct missense mutations. To investigate the pathogenic mechanism underlying LRRK2 dysfunction, we generated a knockin (KI) mouse in which the R1441C mutation is expressed under the control of the endogenous regulatory elements. Homozygous R1441C KI mice appear grossly normal and exhibit no dopaminergic (DA) neurodegeneration or alterations in steady-state levels of striatal dopamine up to 2 years of age. However, these KI mice show reductions in amphetamine (AMPH)-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells. The introduction of the R1441C mutation also impairs dopamine D2 receptor function, as suggested by decreased responses of KI mice in locomotor activity to the inhibitory effect of a D2 receptor agonist, quinpirole. Furthermore, the firing of nigral neurons in R1441C KI mice show reduced sensitivity to suppression induced by quinpirole, dopamine, or AMPH. Together, our data suggest that the R1441C mutation in LRRK2 impairs stimulated dopamine neurotransmission and D2 receptor function, which may represent pathogenic precursors preceding dopaminergic degeneration in PD brains.

    UR - http://www.scopus.com/inward/record.url?scp=70149124508&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=70149124508&partnerID=8YFLogxK

    U2 - 10.1073/pnas.0906334106

    DO - 10.1073/pnas.0906334106

    M3 - Article

    C2 - 19667187

    AN - SCOPUS:70149124508

    VL - 106

    SP - 14622

    EP - 14627

    JO - Proceedings of the National Academy of Sciences of the United States of America

    JF - Proceedings of the National Academy of Sciences of the United States of America

    SN - 0027-8424

    IS - 34

    ER -