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Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents
Journal of comparative neurology (1911), 2014-08, Vol.522 (11), p.2465-2480
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.
2014
Details
Autor(en) / Beteiligte
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.
Titel
Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents
Ist Teil von
Journal of comparative neurology (1911), 2014-08, Vol.522 (11), p.2465-2480
Ort / Verlag
United States: Blackwell Publishing Ltd
Erscheinungsjahr
2014
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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. J. Comp. Neurol. 522:2465–2480, 2014. © 2014 Wiley Periodicals, Inc. Mutations in LRRK2 are the most common known genetic cause of late‐onset Parkinson's disease. The distribution of LRRK2 in the brain has been controversial over the nearly 10 years since the discovery of the protein. Numerous transgenic animals have also been created and described, yet whether they reproduce features of normal anatomical localization of LRRK2 protein has not been studied in any detail. We find that LRRK2 localization differs even between rats and mice, but dramatically differs from normal expression in rodents when LRRK2 is driven from a human LRRK2 promoter. These observations should help guide functional studies to understand LRRK2 in health and disease.
Sprache
Englisch
Identifikatoren
ISSN: 0021-9967
eISSN: 1096-9861
DOI: 10.1002/cne.23583
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4076169
Format
–
Schlagworte
Animals
,
bacterial-artificial chromosome (BAC) transgenics
,
Cerebral Cortex - physiology
,
Chromosomes, Artificial, Bacterial - genetics
,
Corpus Striatum - physiology
,
Gene Knockout Techniques
,
Interneurons - physiology
,
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
,
Male
,
Mice, Inbred C57BL
,
Mice, Knockout
,
Mutation
,
neurodegeneration
,
nigrostriatal circuit
,
Parkinson's disease
,
Promoter Regions, Genetic
,
Protein-Serine-Threonine Kinases - genetics
,
Protein-Serine-Threonine Kinases - metabolism
,
Pyramidal Cells - physiology
,
Rats, Long-Evans
,
Rats, Sprague-Dawley
,
Rats, Transgenic
,
Sequence Alignment
,
Species Specificity
,
Substantia Nigra - physiology
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