Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice

H. L. Melrose, J. C. Dächsel, B. Behrouz, S. J. Lincoln, M. Yue, K. M. Hinkle, C. B. Kent, E. Korvatska, J. P. Taylor, L. Witten, Y. Q. Liang, J. E. Beevers, M. Boules, Brittany Dugger, V. A. Serna, A. Gaukhman, X. Yu, M. Castanedes-Casey, A. T. Braithwaite, S. Ogholikhan & 7 others N. Yu, D. Bass, G. Tyndall, G. D. Schellenberg, D. W. Dickson, C. Janus, M. J. Farrer

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene, first described in 2004 have now emerged as the most important genetic finding in both autosomal dominant and sporadic Parkinson's disease (PD). While a formidable research effort has ensued since the initial gene discovery, little is known of either the normal or the pathological role of LRRK2. We have created lines of mice that express human wild-type (hWT) or G2019S Lrrk2 via bacterial artificial chromosome (BAC) transgenesis. In vivo analysis of the dopaminergic system revealed abnormal dopamine neurotransmission in both hWT and G2019S transgenic mice evidenced by a decrease in extra-cellular dopamine levels, which was detected without pharmacological manipulation. Immunopathological analysis revealed changes in localization and increased phosphorylation of microtubule binding protein tau in G2019S mice. Quantitative biochemical analysis confirmed the presence of differential phospho-tau species in G2019S mice but surprisingly, upon dephosphorylation the tau isoform banding pattern in G2019S mice remained altered. This suggests that other post-translational modifications of tau occur in G2019S mice. We hypothesize that Lrrk2 may impact on tau processing which subsequently leads to increased phosphorylation. Our models will be useful for further understanding of the mechanistic actions of LRRK2 and future therapeutic screening.

Original languageEnglish (US)
Pages (from-to)503-517
Number of pages15
JournalNeurobiology of Disease
Volume40
Issue number3
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

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Microtubule-Associated Proteins
Synaptic Transmission
Transgenic Mice
Leucine
Phosphotransferases
Dopamine
Phosphorylation
Microtubule Proteins
Bacterial Artificial Chromosomes
Gene Transfer Techniques
Genetic Association Studies
Post Translational Protein Processing
Systems Analysis
Carrier Proteins
Protein Isoforms
human LRRK2 protein
Pharmacology
Mutation
Research
Genes

Keywords

  • Anxiety
  • Dopamine
  • Microdialysis
  • Neuropathology
  • Parkinson's disease
  • Transgenic

ASJC Scopus subject areas

  • Neurology

Cite this

Melrose, H. L., Dächsel, J. C., Behrouz, B., Lincoln, S. J., Yue, M., Hinkle, K. M., ... Farrer, M. J. (2010). Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiology of Disease, 40(3), 503-517. https://doi.org/10.1016/j.nbd.2010.07.010

Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. / Melrose, H. L.; Dächsel, J. C.; Behrouz, B.; Lincoln, S. J.; Yue, M.; Hinkle, K. M.; Kent, C. B.; Korvatska, E.; Taylor, J. P.; Witten, L.; Liang, Y. Q.; Beevers, J. E.; Boules, M.; Dugger, Brittany; Serna, V. A.; Gaukhman, A.; Yu, X.; Castanedes-Casey, M.; Braithwaite, A. T.; Ogholikhan, S.; Yu, N.; Bass, D.; Tyndall, G.; Schellenberg, G. D.; Dickson, D. W.; Janus, C.; Farrer, M. J.

In: Neurobiology of Disease, Vol. 40, No. 3, 01.12.2010, p. 503-517.

Research output: Contribution to journalArticle

Melrose, HL, Dächsel, JC, Behrouz, B, Lincoln, SJ, Yue, M, Hinkle, KM, Kent, CB, Korvatska, E, Taylor, JP, Witten, L, Liang, YQ, Beevers, JE, Boules, M, Dugger, B, Serna, VA, Gaukhman, A, Yu, X, Castanedes-Casey, M, Braithwaite, AT, Ogholikhan, S, Yu, N, Bass, D, Tyndall, G, Schellenberg, GD, Dickson, DW, Janus, C & Farrer, MJ 2010, 'Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice', Neurobiology of Disease, vol. 40, no. 3, pp. 503-517. https://doi.org/10.1016/j.nbd.2010.07.010
Melrose, H. L. ; Dächsel, J. C. ; Behrouz, B. ; Lincoln, S. J. ; Yue, M. ; Hinkle, K. M. ; Kent, C. B. ; Korvatska, E. ; Taylor, J. P. ; Witten, L. ; Liang, Y. Q. ; Beevers, J. E. ; Boules, M. ; Dugger, Brittany ; Serna, V. A. ; Gaukhman, A. ; Yu, X. ; Castanedes-Casey, M. ; Braithwaite, A. T. ; Ogholikhan, S. ; Yu, N. ; Bass, D. ; Tyndall, G. ; Schellenberg, G. D. ; Dickson, D. W. ; Janus, C. ; Farrer, M. J. / Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. In: Neurobiology of Disease. 2010 ; Vol. 40, No. 3. pp. 503-517.
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AU - Boules, M.

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