Westerlund M, Belin A C, Anvret A, Bickford P, Olson L, Galter D
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
Neuroscience. 2008 Mar 18;152(2):429-36. doi: 10.1016/j.neuroscience.2007.10.062. Epub 2008 Jan 10.
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.
富含亮氨酸重复激酶2（LRRK2）的突变是帕金森病（PD）最常见的已知病因，可导致家族性和散发性PD。我们在人和大鼠组织的细胞水平上分析了富含亮氨酸重复激酶1（LRRK1）和LRRK2在发育和衰老过程中的时空活性。Lrrk2 mRNA在成年大鼠纹状体、海马、大脑皮层、感觉和交感神经节、肺、脾和肾中表达。通过定量原位杂交发现，在发育中的大鼠纹状体中，Lrrk2转录最早在出生后第8天（P8）观察到，随后在接下来的3周内mRNA水平升高，此后水平一直维持到24个月龄。因此，纹状体中Lrrk2活性的出生后发育时间进程与纹状体多巴胺神经支配的出生后发育密切相关。在P1大鼠的肺、心脏和肾脏中可见Lrrk2 mRNA，而Lrrk1则在P1大鼠的许多区域中发现。Lrrk1存在于成年大鼠的脑、肾上腺、肝脏、肺、脾和肾中，也存在于胚胎脑中，出生后基因活性下降。LRRK1和LRRK2在成年人类大脑皮层、海马以及LRRK2（而非LRRK1）在纹状体中具有活性。在年轻人类胸腺中也可见到这两个基因的转录，并且LRRK2在成年人类肾脏的肾小管部分具有活性。我们的研究结果表明，这两个旁系同源基因在大脑以及包括淋巴组织在内的某些外周器官中具有部分互补的表达模式。虽然Lrrk2在纹状体中的强烈表达与PD相关，但在解读可能的致病途径时，也需要考虑Lrrk2活性的许多其他神经元和非神经元位点。
