Update on the Functional Biology of
            <i>Lrrk2</i>

Melrose, Heather L.

doi:10.2217/14796708.3.6.669

Cited by 31 publications

(43 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MLKs are part of the mitogen activated protein kinase (MAPK) family, and act as MAPK kinase kinases (MAPKKKs) to initiate and transduce a wide range of cell death-relevant responses (Gallo and Johnson, 2002). How and whether LRRK2 acts as a MAPKKK is unclear because the mechanisms through which it is activated, as well as its downstream kinase effects, are not well-characterized (Biskup and West, 2009; Melrose, 2008). …”

Section: Gene and Protein Organizationmentioning

confidence: 99%

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Esteves

Swerdlow

Cardoso

2014

Experimental Neurology

View full text Add to dashboard Cite

Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signalling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD.

show abstract

Section: Gene and Protein Organizationmentioning

confidence: 99%

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Esteves

Swerdlow

Cardoso

2014

Experimental Neurology

View full text Add to dashboard Cite

show abstract

“…Several groups reported kinase activities of the mutants using in vitro kinase assays and found that only the G2019S protein exhibited increased kinase activity, while the other mutants, R1441C, Y1699C and I2020T, showed ambiguous and sometimes conflicting results (18,19,(47)(48)(49). These conflicting data may be due to the use of different substrates in the kinase assays, namely the use of general kinase substrates, such as myelin basic protein or synthetic peptide, or may be due to different enzyme preparations, which were expressed from bacterial, insect, or mammalian cells and used a variety of different tags at either the N-or C-terminal ends (50,51). The increased kinase activity of the G2019S mutant could explain the dominant heredity of that PARK8 mutation.…”

Section: Molecular Biological Features Of Lrrk2 and Its Pathological mentioning

confidence: 99%

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Seol

2010

BMB Reports

View full text Add to dashboard Cite

Parkinson's disease (PD) is the second most common neurodegenerative disease, and 5-10% of the PD cases are genetically inherited as familial PD (FPD). LRRK2 (leucine-rich repeat kinase 2) was first reported in 2004 as a gene corresponding to PARK8, an autosomal gene whose dominant mutations cause familial PD. LRRK2 contains both active kinase and GTPase domains as well as protein-protein interaction motifs such as LRR (leucine-rich repeat) and WD40. Most pathogenic LRRK2 mutations are located in either the GTPase or kinase domain, implying important roles for the enzymatic activities in PD pathogenic mechanisms. In comparison to other PD causative genes such as parkin and PINK1, LRRK2 exhibits two important features. One is that LRRK2's mutations (especially the G2019S mutation) were observed in sporadic as well as familial PD patients. Another is that, among the various PDcausing genes, pathological characteristics observed in patients carrying LRRK2 mutations are the most similar to patients with sporadic PD. Because of these two observations, LRRK2 has been intensively investigated for its pathogenic mechanism (s) and as a target gene for PD therapeutics. In this review, the general biochemical and molecular features of LRRK2, the recent results of LRRK2 studies and LRRK2's therapeutic potential as a PD target gene will be discussed. [BMB reports 2010; 43(4): 233-244]

show abstract

“…Whereas motor symptoms may be managed with dopamine replacement therapy in the earlier stages of the disease, no disease-modifying therapy exists. Leucine-rich repeat kinase 2 (LRRK2) has been identified as a potential target for disease-modifying therapy because mutations in the catalytic core of LRRK2 have been associated with both autosomal-dominant and late-onset sporadic PD (1)(2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Effect of selective LRRK2 kinase inhibition on nonhuman primate lung

Fuji¹,

Flagella²,

Baca³

et al. 2015

Sci. Transl. Med.

311

293

View full text Add to dashboard Cite

Inhibition of the kinase activity of leucine-rich repeat kinase 2 (LRRK2) is under investigation as a possible treatment for Parkinson's disease. However, there is no clinical validation as yet, and the safety implications of targeting LRRK2 kinase activity are not well understood. We evaluated the potential safety risks by comparing human and mouse LRRK2 mRNA tissue expression, by analyzing a Lrrk2 knockout mouse model, and by testing selective brain-penetrating LRRK2 kinase inhibitors in multiple species. LRRK2 mRNA tissue expression was comparable between species. Phenotypic analysis of Lrrk2 knockout mice revealed morphologic changes in lungs and kidneys, similar to those reported previously. However, in preclinical toxicity assessments in rodents, no pulmonary or renal changes were induced by two distinct LRRK2 kinase inhibitors. Both of these kinase inhibitors induced abnormal cytoplasmic accumulation of secretory lysosome-related organelles known as lamellar bodies in type II pneumocytes of the lung in nonhuman primates, but no lysosomal abnormality was observed in the kidney. The pulmonary change resembled the phenotype of Lrrk2 knockout mice, suggesting that this was LRRK2-mediated rather than a nonspecific or off-target effect. A biomarker of lysosomal dysregulation, di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP), was also decreased in the urine of Lrrk2 knockout mice and nonhuman primates treated with LRRK2 kinase inhibitors. Our results suggest a role for LRRK2 in regulating lysosome-related lamellar bodies and that pulmonary toxicity may be a critical safety liability for LRRK2 kinase inhibitors in patients.

show abstract

Update on the Functional Biology of Lrrk2

Cited by 31 publications

References 92 publications

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Effect of selective LRRK2 kinase inhibition on nonhuman primate lung

Contact Info

Product

Resources

About