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 language | English (US) |
|---|---|
| Pages (from-to) | 2465-2480 |
| Number of pages | 16 |
| Journal | Journal of Comparative Neurology |
| Volume | 522 |
| Issue number | 11 |
| DOIs | |
| State | Published - Aug 1 2014 |
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Keywords
- Bacterial-artificial chromosome (BAC) transgenics
- Neurodegeneration
- Nigrostriatal circuit
- Parkinson's disease
ASJC Scopus subject areas
- Neuroscience(all)
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents
AU - West, Andrew B.
AU - Cowell, Rita M.
AU - Daher, João P L
AU - Moehle, Mark S.
AU - Hinkle, Kelly M.
AU - Melrose, Heather L
AU - Standaert, David G.
AU - Volpicelli-Daley, Laura A.
PY - 2014/8/1
Y1 - 2014/8/1
N2 - 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.
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.
KW - Bacterial-artificial chromosome (BAC) transgenics
KW - Neurodegeneration
KW - Nigrostriatal circuit
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=84901648685&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901648685&partnerID=8YFLogxK
U2 - 10.1002/cne.23583
DO - 10.1002/cne.23583
M3 - Article
C2 - 24633735
AN - SCOPUS:84901648685
VL - 522
SP - 2465
EP - 2480
JO - Journal of Comparative Neurology
JF - Journal of Comparative Neurology
SN - 0021-9967
IS - 11
ER -