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Research Articles, Neurobiology of Disease

Motor Impairments and Dopaminergic Defects Caused by Loss of Leucine-Rich Repeat Kinase Function in Mice

Guodong Huang, Daniel W. Bloodgood, Jongkyun Kang, Anu Shahapal, Phoenix Chen, Konstantin Kaganovsky, Jae-Ick Kim, Jun B. Ding and Jie Shen
Journal of Neuroscience 8 June 2022, 42 (23) 4755-4765; DOI: https://doi.org/10.1523/JNEUROSCI.0140-22.2022
Guodong Huang
1Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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Daniel W. Bloodgood
3Departments of Neurosurgery and
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Jongkyun Kang
1Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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Anu Shahapal
1Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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Phoenix Chen
1Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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Konstantin Kaganovsky
3Departments of Neurosurgery and
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Jae-Ick Kim
3Departments of Neurosurgery and
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Jun B. Ding
3Departments of Neurosurgery and
4Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305
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Jie Shen
1Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
2Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115
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Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD), but the pathogenic mechanism underlying LRRK2 mutations remains unresolved. In this study, we investigate the consequence of inactivation of LRRK2 and its functional homolog LRRK1 in male and female mice up to 25 months of age using behavioral, neurochemical, neuropathological, and ultrastructural analyses. We report that LRRK1 and LRRK2 double knock-out (LRRK DKO) mice exhibit impaired motor coordination at 12 months of age before the onset of dopaminergic neuron loss in the substantia nigra (SNpc). Moreover, LRRK DKO mice develop age-dependent, progressive loss of dopaminergic terminals in the striatum. Evoked dopamine (DA) release measured by fast-scan cyclic voltammetry in the dorsal striatum is also reduced in the absence of LRRK. Furthermore, LRRK DKO mice at 20–25 months of age show substantial loss of dopaminergic neurons in the SNpc. The surviving SNpc neurons in LRRK DKO mice at 25 months of age accumulate large numbers of autophagic and autolysosomal vacuoles and are accompanied with microgliosis. Surprisingly, the cerebral cortex is unaffected, as shown by normal cortical volume and neuron number as well as unchanged number of apoptotic cells and microglia in LRRK DKO mice at 25 months. These findings show that loss of LRRK function causes impairments in motor coordination, degeneration of dopaminergic terminals, reduction of evoked DA release, and selective loss of dopaminergic neurons in the SNpc, indicating that LRRK DKO mice are unique models for better understanding dopaminergic neurodegeneration in PD.

SIGNIFICANCE STATEMENT Our current study employs a genetic approach to uncover the normal function of the LRRK family in the brain during mouse life span. Our multidisciplinary analysis demonstrates a critical normal physiological role of LRRK in maintaining the integrity and function of dopaminergic terminals and neurons in the aging brain, and show that LRRK DKO mice recapitulate several key features of PD and provide unique mouse models for elucidating molecular mechanisms underlying dopaminergic neurodegeneration in PD.

  • dopamine release
  • knock-out mice
  • LRRK2
  • Parkinson's disease
  • SNpc
  • striatum

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The Journal of Neuroscience: 42 (23)
Journal of Neuroscience
Vol. 42, Issue 23
8 Jun 2022
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Motor Impairments and Dopaminergic Defects Caused by Loss of Leucine-Rich Repeat Kinase Function in Mice
Guodong Huang, Daniel W. Bloodgood, Jongkyun Kang, Anu Shahapal, Phoenix Chen, Konstantin Kaganovsky, Jae-Ick Kim, Jun B. Ding, Jie Shen
Journal of Neuroscience 8 June 2022, 42 (23) 4755-4765; DOI: 10.1523/JNEUROSCI.0140-22.2022

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Motor Impairments and Dopaminergic Defects Caused by Loss of Leucine-Rich Repeat Kinase Function in Mice
Guodong Huang, Daniel W. Bloodgood, Jongkyun Kang, Anu Shahapal, Phoenix Chen, Konstantin Kaganovsky, Jae-Ick Kim, Jun B. Ding, Jie Shen
Journal of Neuroscience 8 June 2022, 42 (23) 4755-4765; DOI: 10.1523/JNEUROSCI.0140-22.2022
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Keywords

  • dopamine release
  • knock-out mice
  • LRRK2
  • Parkinson's disease
  • SNpc
  • striatum

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