Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

M. Yue, K. M. Hinkle, P. Davies, Eugenia D Trushina, Fabienne Fiesel, T. A. Christenson, A. S. Schroeder, Lizhi Zhang, E. Bowles, B. Behrouz, S. J. Lincoln, J. E. Beevers, A. J. Milnerwood, A. Kurti, Pamela J McLean, John D. Fryer, Wolfdieter Springer, Dennis W Dickson, M. J. Farrer, Heather L Melrose

Research output: Contribution to journalArticle

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Abstract

Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24. months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6. months, by 12. months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

Original languageEnglish (US)
Pages (from-to)172-195
Number of pages24
JournalNeurobiology of Disease
Volume78
DOIs
StatePublished - Jun 1 2015

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Mutation
Dopamine
Phosphotransferases
Mitochondrial Dynamics
Microdialysis
Neurotransmitter Agents
Parkinson Disease
Disease Progression
Maintenance
Genome
Brain
Pharmaceutical Preparations
Genes
Late Onset Disorders

Keywords

  • Dopamine
  • Gene-targeted mouse model
  • Microdialysis
  • Mitochondria
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology

Cite this

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. / Yue, M.; Hinkle, K. M.; Davies, P.; Trushina, Eugenia D; Fiesel, Fabienne; Christenson, T. A.; Schroeder, A. S.; Zhang, Lizhi; Bowles, E.; Behrouz, B.; Lincoln, S. J.; Beevers, J. E.; Milnerwood, A. J.; Kurti, A.; McLean, Pamela J; Fryer, John D.; Springer, Wolfdieter; Dickson, Dennis W; Farrer, M. J.; Melrose, Heather L.

In: Neurobiology of Disease, Vol. 78, 01.06.2015, p. 172-195.

Research output: Contribution to journalArticle

Yue, M, Hinkle, KM, Davies, P, Trushina, ED, Fiesel, F, Christenson, TA, Schroeder, AS, Zhang, L, Bowles, E, Behrouz, B, Lincoln, SJ, Beevers, JE, Milnerwood, AJ, Kurti, A, McLean, PJ, Fryer, JD, Springer, W, Dickson, DW, Farrer, MJ & Melrose, HL 2015, 'Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice', Neurobiology of Disease, vol. 78, pp. 172-195. https://doi.org/10.1016/j.nbd.2015.02.031
Yue, M. ; Hinkle, K. M. ; Davies, P. ; Trushina, Eugenia D ; Fiesel, Fabienne ; Christenson, T. A. ; Schroeder, A. S. ; Zhang, Lizhi ; Bowles, E. ; Behrouz, B. ; Lincoln, S. J. ; Beevers, J. E. ; Milnerwood, A. J. ; Kurti, A. ; McLean, Pamela J ; Fryer, John D. ; Springer, Wolfdieter ; Dickson, Dennis W ; Farrer, M. J. ; Melrose, Heather L. / Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. In: Neurobiology of Disease. 2015 ; Vol. 78. pp. 172-195.
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abstract = "Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24. months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6. months, by 12. months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.",
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AU - Fiesel, Fabienne

AU - Christenson, T. A.

AU - Schroeder, A. S.

AU - Zhang, Lizhi

AU - Bowles, E.

AU - Behrouz, B.

AU - Lincoln, S. J.

AU - Beevers, J. E.

AU - Milnerwood, A. J.

AU - Kurti, A.

AU - McLean, Pamela J

AU - Fryer, John D.

AU - Springer, Wolfdieter

AU - Dickson, Dennis W

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AU - Melrose, Heather L

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