Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: Implications for Parkinson's disease.
Mutations in leucine-rich repeat kinase 2 (LRRK2) constitute the most common known cause of Parkinson's disease (PD), accounting for both familial and sporadic forms of the disease. We analyzed the tempo-spatial activity of leucine-rich repeat kinase 1 (LRRK1) and LRRK2 at the cellular level in human and rat tissues including development and aging. Lrrk2 mRNA is expressed in adult rat striatum, hippocampus, cerebral cortex, sensory and sympathetic ganglia, lung, spleen and kidney. In the developing rat striatum, Lrrk2 transcription is first observed at postnatal day (P) 8 followed by increasing mRNA levels during the following 3 weeks, as revealed by quantitative in situ hybridization, after which levels remain up to 24 months of age. The time-course of postnatal development of Lrrk2 activity in striatum thus closely mirrors the postnatal development of the dopamine innervation of striatum. Lrrk2 mRNA is seen in P1 rat lung, heart, and kidney, whereas Lrrk1 is found in many areas of the P1 rat. Lrrk1 is present in adult rat brain, adrenal gland, liver, lung, spleen and kidney and also in embryonic brain, with declining gene activity after birth. LRRK1 and LRRK2 are active in the adult human cortex cerebri, hippocampus and LRRK2, but not LRRK1, in striatum. Transcription of both genes is also seen in the young human thymus and LRRK2 is active in tubular parts of the adult human kidney. Our findings suggest that the two paralogous genes have partly complementary expression patterns in the brain, as well as in certain peripheral organs including lymphatic tissues. While the strong presence of Lrrk2 message in striatum is intriguing in relation to PD, the many other neuronal and non-neuronal sites of Lrrk2 activity also needs to be taken into account in deciphering possible pathogenic pathways.
Westerlund
M
M
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
Belin
A C
AC
Anvret
A
A
Bickford
P
P
Olson
L
L
Galter
D
D
D000328:Adult; D000367:Age Factors; D000368:Aged; D000825:Animal Structures / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013950:Thymus Gland / Q000378:metabolism
C510751:LRRK1 protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases