Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons

Wang, Danling; Tang, Beisha; Zhao, Guohua; Pan, Qian; Xia, Kun; Bodmer, Rolf; Zhang, Zhuohua

doi:10.1186/1750-1326-3-3

Cited by 114 publications

(128 citation statements)

References 27 publications

(26 reference statements)

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“…Drosophila LRRK2 models were also developed (21,97,98). Loss-of-function dLRRK mutants in Drosophila yielded conflicting results on locomotive motor impairment (21,97).…”

Section: Normal and Pathological Features Of Lrrk2mentioning

confidence: 99%

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

Seol

2010

BMB Reports

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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]

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“…Drosophila LRRK2 models were also developed (21,97,98). Loss-of-function dLRRK mutants in Drosophila yielded conflicting results on locomotive motor impairment (21,97).…”

Section: Normal and Pathological Features Of Lrrk2mentioning

confidence: 99%

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

Seol

2010

BMB Reports

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“…A second study using the same fly line did not detect motor impairment and also showed that dLRRK loss-of-function flies are resistant to the mitochondrial toxins rotenone and paraquat, but are more sensitive to general oxidative stress, suggesting a role for dLRRK in mitochondria [76]. Overexpression of dLRRKWT or Roc domain substitution R1069C (comparable to Lrrk2 R1441C in humans) using a number of different GAL4 drivers (directed to muscle, whole-body and dopaminergic neurons) produced no deleterious effects [75].…”

Section: Fly Modelsmentioning

confidence: 95%

Update on the Functional Biology of Lrrk2

Melrose

2008

Future Neurol.

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The etiology of Parkinson's disease (PD) was long thought to be due to environmental factors. Following the discovery of autosomal-dominant mutations in the α-synuclein gene, and later recessive mutations in the DJ-1, Parkin and PINK-1 genes, the field of PD genetics exploded. In 2004, it was discovered that mutations in the PARK8 locus -leucine-rich repeat kinase 2 (LRRK2, Lrrk2) -are the most important genetic cause of autosomal-dominant PD. Lrrk2 substitutions also account for sporadic PD in certain ethnic populations and have been shown to increase the risk of PD in Asian populations. Drug therapies targeting Lrrk2 activity may therefore be beneficial to both familial and sporadic PD patients, hence understanding the role of Lrrk2 in health and disease is critical. This review aims to highlight the research effort concentrated on elucidating the functional biological role of Lrrk2, and to provide some future therapeutic perspectives.

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“…63,66 In contrast, knocking out LRRK2 has no effect on dopaminergic neuronal development or maintenance. 67 Moreover, LRRK2 transgenic mouse models do not show the further pathological results, which is unclear. 15 Parkin, phosphatase, and tensin homologinduced novel kinase 1, and DJ-1…”

Section: Leucine-rich Repeat Kinase 2 Mutationsmentioning

confidence: 99%

Animal models of Parkinson's disease and their applications

Park

Zhao²,

Lee

2016

JPRLS

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Abstract:Parkinson's disease (PD) is a progressive neurodegenerative disorder that occurs mainly due to the degeneration of dopaminergic neuronal cells in the substantia nigra. l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective known therapy for PD. However, chronic l-DOPA administration results in a loss of drug efficacy and irreversible adverse effects, including l-DOPA-induced dyskinesia, affective disorders, and cognitive function disorders. To study the motor and non-motor symptomatic dysfunctions in PD, neurotoxin and genetic animal models of PD have been widely applied. However, these animal models do not exhibit all of the pathophysiological symptoms of PD. Regardless, neurotoxin rat and mouse models of PD have been commonly used in the development of bioactive components from natural herbal medicines. Here, the main animal models of PD and their applications have been introduced in order to aid the development of therapeutic and adjuvant agents.

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Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons

Cited by 114 publications

References 27 publications

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

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

Update on the Functional Biology of Lrrk2

Animal models of Parkinson's disease and their applications

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Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons

Cited by 114 publications

References 27 publications

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

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

Update on the Functional Biology of Lrrk2

Animal models of Parkinson&#39;s disease and their applications

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Product

Resources

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Animal models of Parkinson's disease and their applications