Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human leucine-rich repeat kinase 1 (LRRK1) is a multi-domain protein of unknown function belonging to the ROCO family of complex proteins. Here, we report the molecular characterization of human LRRK1 and show, for the first time, that LRRK1 is both a functional protein kinase and a GDP/GTP-binding protein. Binding of GTP to LRRK1 is specific, requires the GTPase-like Roc domain, and leads to a stimulation of LRRK1 kinase activity. LRRK1 is the first example of a GTP-regulated protein kinase harboring both the kinase effector domain and the GTP-binding regulatory domain. Hence, we propose a model in which LRRK1 cycles between a GTP-bound active and a GDP-bound inactive state. Moreover, we mutated LRRK1 to mimic mutations previously identified in LRRK2/dardarin, the only human paralogue of LRRK1, that have been linked to autosomal-dominant parkinsonism. We demonstrate that three of four mutations analyzed significantly downregulate LRRK1 kinase activity. Ultimately, the results presented for LRRK1 may contribute to the elucidation of LRRK2's role in the pathogenesis of Parkinson's disease.
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PMID:LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain. 1624 88

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.
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PMID: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. 1827 92

Mutations in LRRK2 (leucine-rich repeat kinase 2) are associated with both familial and sporadic PD (Parkinson's disease). LRRK1 (leucine-rich repeat kinase 1) shares a similar domain structure with LRRK2, but it is not linked to PD. LRRK proteins belong to a gene family known as ROCO, which codes for large proteins with several domains. All ROCO proteins have a ROC (Ras of complex proteins) GTPase domain followed by a domain of unknown function [COR (C-terminal of ROC)]. LRRK2, LRRK1 and other ROCO proteins also possess a kinase domain. To date, the function of LRRK1 and both the physiological and the pathological roles of LRRK2 are only beginning to unfold. The comparative analysis of these two proteins is a strategy to single out the specific properties of LRRKs to understand their cellular physiology. This comparison is the starting point to unravel the pathways that may lead to PD and eventually to develop therapeutic strategies for its treatment. In the present review, we discuss recently published results on LRRK2 and its paralogue LRRK1 concerning their evolutionary significance, biochemical properties and potential functional roles.
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PMID:Human leucine-rich repeat kinase 1 and 2: intersecting or unrelated functions? 2298 72