Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents

Andrew B. West, Rita M. Cowell, João P L Daher, Mark S. Moehle, Kelly M. Hinkle, Heather L Melrose, David G. Standaert, Laura A. Volpicelli-Daley

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are found in a significant proportion of late-onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared with mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2-G2019S protein from mouse bacterial artificial chromosome (BAC) constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2-G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and nonhuman primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate-specific promoter sequence that does not exist in lower mammalian species. These noncoding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies.

Original languageEnglish (US)
Pages (from-to)2465-2480
Number of pages16
JournalJournal of Comparative Neurology
Volume522
Issue number11
DOIs
StatePublished - Aug 1 2014

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Substantia Nigra
Leucine
Rodentia
Phosphotransferases
Bacterial Artificial Chromosomes
Human Artificial Chromosomes
Parkinson Disease
Primates
Brain
Neurons
Corpus Striatum
Pyramidal Cells
Interneurons
Cholinergic Agents
Monoclonal Antibodies

Keywords

  • Bacterial-artificial chromosome (BAC) transgenics
  • Neurodegeneration
  • Nigrostriatal circuit
  • Parkinson's disease

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

West, A. B., Cowell, R. M., Daher, J. P. L., Moehle, M. S., Hinkle, K. M., Melrose, H. L., ... Volpicelli-Daley, L. A. (2014). Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. Journal of Comparative Neurology, 522(11), 2465-2480. https://doi.org/10.1002/cne.23583

Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. / West, Andrew B.; Cowell, Rita M.; Daher, João P L; Moehle, Mark S.; Hinkle, Kelly M.; Melrose, Heather L; Standaert, David G.; Volpicelli-Daley, Laura A.

In: Journal of Comparative Neurology, Vol. 522, No. 11, 01.08.2014, p. 2465-2480.

Research output: Contribution to journalArticle

West, AB, Cowell, RM, Daher, JPL, Moehle, MS, Hinkle, KM, Melrose, HL, Standaert, DG & Volpicelli-Daley, LA 2014, 'Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents', Journal of Comparative Neurology, vol. 522, no. 11, pp. 2465-2480. https://doi.org/10.1002/cne.23583
West, Andrew B. ; Cowell, Rita M. ; Daher, João P L ; Moehle, Mark S. ; Hinkle, Kelly M. ; Melrose, Heather L ; Standaert, David G. ; Volpicelli-Daley, Laura A. / Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. In: Journal of Comparative Neurology. 2014 ; Vol. 522, No. 11. pp. 2465-2480.
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abstract = "Mutations in leucine-rich repeat kinase 2 (LRRK2) are found in a significant proportion of late-onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared with mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2-G2019S protein from mouse bacterial artificial chromosome (BAC) constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2-G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and nonhuman primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate-specific promoter sequence that does not exist in lower mammalian species. These noncoding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies.",
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AU - Melrose, Heather L

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AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are found in a significant proportion of late-onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared with mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2-G2019S protein from mouse bacterial artificial chromosome (BAC) constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2-G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and nonhuman primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate-specific promoter sequence that does not exist in lower mammalian species. These noncoding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies.

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