LRRK2 in Parkinson's disease: protein domains and functional insights

Mata, Ignacio; Wedemeyer, William J.; Farrer, Matthew J.; Taylor, Julie P.; Gallo, Kathleen A.

doi:10.1016/j.tins.2006.03.006

Cited by 438 publications

(413 citation statements)

References 75 publications

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“…I used the patterns deduced from the human and S. purpuratus LRRK2 proteins to search for similarities in other proteins but did not detect any significant match. On the contrary, Mata et al (2006) suggested, without any indication of how they obtained the evidence, that the N-terminal region of human LRRK2 contains a set of armadillo repeats. I decided to check for this possibility using the set of 10 sequences shown in Fig.…”

Section: Resultsmentioning

confidence: 98%

“…LRRK2 is the first gene whose mutations have been consistently associated with both the familial and the much more frequent sporadic cases of PD. Dominant mutations in LRRK2 may explain 13% of the familial and up to 5% of sporadic PD cases (Berg et al 2005;Mata et al 2006;Taylor et al 2006). This general involvement of the LRRK2 gene in both types of PD suggests a central role in dopaminergic cell death and the onset of the disease Taylor et al 2006).…”

Section: Introductionmentioning

confidence: 99%

“…LRRK2 protein has a complex structure, which includes several types of repeats and three large domains, called the Roc, COR, and kinase domains (Bosgraaf and Van Hastert 2003;Marín 2006;Mata et al 2006). Proteins with a Roc domain, which is a Ras-like GTPase domain, plus a COR domain, a characteristic domain of unknown function, belong to the Roco family (Bosgraaf and Van Hastert 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ancient Origin of the Parkinson Disease Gene LRRK2

Marı́n

2008

J Mol Evol

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Dominant mutations in the LRRK2 gene, a member of the Roco family, cause both familial and sporadic Parkinson disease. LRRK genes had so far been detected only in bilaterian animals. In deuterostomes, including humans, two LRRK genes (LRRK1 and LRRK2) exist, while in protostomes a single LRRK gene has been found. In this study, I combine structural and phylogenetic analyses to show that the cnidarian Nematostella vectensis has four LRRK genes. One of them is a bona fide orthologue of the human LRRK2 gene, demonstrating that this gene has an ancient origin. Two others are, respectively, orthologues of the deuterostome LRRK1 and the protostome LRRK genes. The fourth gene is probably cnidarian-specific. This precise characterization of the early evolution of LRRK genes in animals has important implications, because it indicates that the Drosophila and Caenorhabditis LRRK genes, which are studied to gain an understanding of LRRK2 function, are not true orthologues of the human Parkinson disease gene. Novel functional insights are also gained by comparison of the structures of LRRK2 genes in distantly related species.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ancient Origin of the Parkinson Disease Gene LRRK2

Marı́n

2008

J Mol Evol

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“…The LRRK2 gene encodes a large multidomain protein with 2527 amino acids, the physiological function of which is currently unknown. However, there are numerous functional domains associated with this protein, including a leucineͲrich repeat (LRR)domain, a Ras of complex protein (Roc) GTPase domain followed by its associated CͲterminal of Roc (COR) domain, a kinase domain of the tyrosine kinaseͲlike (TKL) subfamily, homologous to other mitogenͲactivated protein kinase kinase kinase (MAPKKK), and a CͲterminal WD40 domain [195] (Figure 2). This combination of motifs is highly conserved in vertebrates [196], however, LRRK2 is unusual, since it encodes two distinct enzymes, kinase and GTPase in the same molecule.…”

Section: Leucineǧrich Repeat Kinase 2 (Lrrk2)mentioning

confidence: 99%

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2012

Free Radical Biology and Medicine

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“…The LRRK2 gene encodes a large multidomain protein with 2527 amino acids, the physiological function of which is currently unknown. However, there are numerous functional domains associated with this protein, including a leucine-rich repeat (LRR) domain, a Ras of complex protein (Roc) GTPase domain followed by its associated C-terminal of Roc domain, a kinase domain of the tyrosine kinase-like subfamily homologous to other mitogen-activated protein kinase kinase kinases, and a C-terminal WD40 domain [195] (Fig. 2).…”

Section: Leucine-rich Repeat Kinase 2 (Lrrk2)mentioning

confidence: 99%

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2013

Free Radical Biology and Medicine

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a b s t r a c tParkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of a-synuclein (a-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to a-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves a-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity.

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LRRK2 in Parkinson's disease: protein domains and functional insights

Cited by 438 publications

References 75 publications

Ancient Origin of the Parkinson Disease Gene LRRK2

Ancient Origin of the Parkinson Disease Gene LRRK2

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

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