The Familial Parkinsonism Gene LRRK2 Regulates Neurite Process Morphology

MacLeod, David; Dowman, J; Hammond, Rachel; Leete, Thomas; Inoue, Keiichi; Abeliovich, Asa

doi:10.1016/j.neuron.2006.10.008

Cited by 532 publications

(665 citation statements)

References 17 publications

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“…SakaguchiNakashima et al (2007) showed that mutations in the C. elegans LRK-1 gene, the only LRRK gene present in this species, generate anomalies in the localization of synaptic vesicle proteins. This result, which involves LRRK gene products in the regulation of vesicular transport, agrees with functional data for human LRRK2, which implicates it in synaptic vesicle recycling and neurite outgrowth (MacLeod et al 2006;Hatano et al 2007). Even more striking were the results obtained by Lee et al (2007), showing that loss of function of the LRKK gene of D. melanogaster leads to the death of dopaminergic neurons in the fly brain and anomalies in locomotor activity.…”

Section: Discussionsupporting

confidence: 87%

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: Discussionsupporting

confidence: 87%

Ancient Origin of the Parkinson Disease Gene LRRK2

Marı́n

2008

J Mol Evol

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“…When expressed in neuroblastoma cell line or cultured cortical neurons, mutant (G2019S) LRRK2 has been shown to induce apoptotic cell death by activating caspase-3 and caspase-8. [37][38][39] Our results provide the first in-vivo evidence that mutant (G2019S) LRRK2 causes the cell death of SN dopaminergic neurons by activating caspase-9 and caspase-8 through MKK4-JNK-c-Jun pathway.…”

Section: Discussionmentioning

confidence: 62%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

154

151

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(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve-to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser 257 , and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63 , downstream targets of phospho-MKK4 Ser257 , was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63 , and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.

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“…LRRK2 was found to be associated with membranous structures and vesicles in the mammalian brain 120 and enriched in the Golgi complex 42, 94 at the extent that mice with wild‐type and G2019S ‐LRRK2 overexpression presented fragmentation of the Golgi complex 121.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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The Familial Parkinsonism Gene LRRK2 Regulates Neurite Process Morphology

Cited by 532 publications

References 17 publications

Ancient Origin of the Parkinson Disease Gene LRRK2

Ancient Origin of the Parkinson Disease Gene LRRK2

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Cellular processes associated with LRRK2 function and dysfunction

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