TY  - JOUR
AU  - Giesert, Florian
AU  - Hofmann, Andreas
AU  - Bürger, Alexander
AU  - Zerle, Julia
AU  - Kloos, Karina
AU  - Hafen, Ulrich
AU  - Ernst, Luise
AU  - Zhang, Jingzhong
AU  - Vogt-Weisenhorn, Daniela Maria
AU  - Wurst, Wolfgang
TI  - Expression analysis of Lrrk1, Lrrk2 and Lrrk2 splice variants in mice.
JO  - PLOS ONE
VL  - 8
IS  - 5
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-03231
SP  - e63778
PY  - 2013
AB  - Missense mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). In order to get insights into the physiological role of Lrrk2, we examined the distribution of Lrrk2 mRNA and different splice variants in the developing murine embryo and the adult brain of Mus musculus. To analyse if the Lrrk2-paralog, Lrrk1, may have redundant functions in PD-development, we also compared Lrrk1 and Lrrk2 expression in the same tissues. Using radioactive in situ hybridization, we found ubiquitous expression of both genes at low level from embryonic stage E9.5 onward, which progressively increased up until birth. The developing central nervous system (CNS) displayed no prominent Lrrk2 mRNA signals at these time-points. However, in the entire postnatal brain Lrrk2 became detectable, showing strongest level in the striatum and the cortex of adult mice; Lrrk1 was only detectable in the mitral cell layer of the olfactory bulb. Thus, due to the non-overlapping expression patterns, a redundant function of Lrrk2 and Lrrk1 in the pathogenesis of PD seems to be unlikely. Quantification of Lrrk2 mRNA and protein level in several brain regions by real-time PCR and Western blot verified the striatum and cortex as hotspots of postnatal Lrrk2 expression. Strong expression of Lrrk2 is mainly found in neurons, specifically in the dopamine receptor 1 (DRD1a) and 2 (DRD2)-positive subpopulations of the striatal medium spiny neurons. Finally, we identified 2 new splice-variants of Lrrk2 in RNA-samples from various adult brain regions and organs: a variant with a skipped exon 5 and a truncated variant terminating in an alternative exon 42a. In order to identify the origin of these two splice variants, we also analysed primary neural cultures independently and found cell-specific expression patterns for these variants in microglia and astrocytes.
KW  - Alternative Splicing
KW  - Animals
KW  - Brain: metabolism
KW  - Embryonic Development: genetics
KW  - Gene Expression Profiling
KW  - Gene Expression Regulation, Developmental
KW  - Gene Order
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
KW  - Mice
KW  - Neurons: metabolism
KW  - Protein-Serine-Threonine Kinases: genetics
KW  - Protein-Serine-Threonine Kinases: metabolism
KW  - RNA, Messenger: genetics
KW  - RNA, Messenger: metabolism
KW  - RNA, Messenger (NLM Chemicals)
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
KW  - Lrrk1 protein, mouse (NLM Chemicals)
KW  - Lrrk2 protein, mouse (NLM Chemicals)
KW  - Protein-Serine-Threonine Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23675505
C2  - pmc:PMC3651128
DO  - DOI:10.1371/journal.pone.0063778
UR  - https://pub.dzne.de/record/136909
ER  -