Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease

Venderová, Kateřina; Kabbach, Ghassan; Abdel-Messih, Elizabeth; Zhang, Yi; Parks, Robin J.; Imai, Yuzuru; Gehrke, Stephan; Ngsee, Johnny K.; LaVoie, Matthew J.; Slack, Ruth S.; Rao, Yong; Zhang, Zhuohua; Lu, Bingwei; Haque, M. Emdadul; Park, David

doi:10.1093/hmg/ddp394

Cited by 165 publications

(142 citation statements)

References 29 publications

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“…Venderova et al (2009) report the genetic interaction between LRRK2 and PINK1 in Drosophila eyes. Consistently, mutant LRRK2 can activate pathologic JNK signaling via MAPKKs, and Parkin inhibits JNK in an E3 ligase activitydependent manner; these findings imply crosstalk between LRRK2 and PINK1 (Cha et al, 2005;Gloeckner et al, 2009;Hwang et al, 2010).…”

Section: Sir2 and Foxo As Novel Partners Of Pink1mentioning

confidence: 98%

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Koh

Chung

2012

Molecules and Cells

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Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an agedependent selective loss of dopaminergic (DA) neurons. Although most PD cases are sporadic, more than 20 responsible genes in familial cases were identified recently. Genetic studies using Drosophila models demonstrate that PINK1, a mitochondrial kinase encoded by a PD-linked gene PINK1, is critical for maintaining mitochondrial function and integrity. This suggests that mitochondrial dysfunction is the main cause of PD pathogenesis. Further genetic and cell biological studies revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase encoded by another PD-linked gene parkin, to mitochondria and regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of various mitochondrial proteins. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently inhibiting mitochondrial transport and mitochondrial oxidative damage, respectively. Moreover, recent Drosophila genetic analyses demonstrate that the neuroprotective molecules Sir2 and FOXO specifically complement mitochondrial dysfunction and DA neuron loss in PINK1 null mutants, suggesting that Sir2 and FOXO protect mitochondria and DA neurons downstream of PINK1. Collectively, these recent results suggest that PINK1 plays multiple roles in mitochondrial quality control by regulating its mitochondrial, cytosolic, and nuclear targets.

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Section: Sir2 and Foxo As Novel Partners Of Pink1mentioning

confidence: 98%

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Koh

Chung

2012

Molecules and Cells

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“…In Drosophila, a dLRRK Y1383C mutant (analogous to human Y1699C) caused prominent vesicular aggregation of the protein and DA neuron loss [75]. Transgenic overexpression of human Y1699C or G2385R LRRK2 in Drosophila is also associated with DA neuron loss accompanied by locomotor deficits [117,122].…”

Section: Direct Toxic Effects Of Lrrk2 Expression In Neuronsmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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“…Several reports suggested that LRRK2 interacts with Parkin, DJ-1 or PINK-1 in mammalian cell lines, C. elegans, and Drosophila melanogaster models of Parkinson's disease (82)(83)(84). Another recent study revealed that over-expression of LRRK2 accelerates the progression of neuropathological phenotypes in transgenic mice with the A53T α-synuclein mutation (85).…”

Section: Proteins Interacting With 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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Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease

Cited by 165 publications

References 29 publications

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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

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