Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration

Smith, Wanli W.; Pei, Zhong; Jiang, Haibing; Moore, Darren J.; Liang, Yideng; West, Andrew B.; Dawson, Valina L.; Dawson, Ted M.; Ross, Christopher A.

doi:10.1073/pnas.0508052102

Cited by 382 publications

(334 citation statements)

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“…It has also been reported that expression of pathogenic LRRK2 mutants (R1441C, Y1699C, or G2019S) results in neuronal degeneration and protein aggregation or inclusions in SH-SY5Y cells and cultured cortical neurons (11,14,15). LRRK2 has also been implicated in the biogenesis and/or regulation of intracellular membrane structures (16), synaptic vesicle endocytosis (17), and neurite outgrowth (15).…”

mentioning

confidence: 99%

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Tong

Pisani

Martella

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

275

267

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Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease (PD). The importance of the R1441 residue in the pathogenesis is highlighted by the identification of three distinct missense mutations. To investigate the pathogenic mechanism underlying LRRK2 dysfunction, we generated a knockin (KI) mouse in which the R1441C mutation is expressed under the control of the endogenous regulatory elements. Homozygous R1441C KI mice appear grossly normal and exhibit no dopaminergic (DA) neurodegeneration or alterations in steady-state levels of striatal dopamine up to 2 years of age. However, these KI mice show reductions in amphetamine (AMPH)-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells. The introduction of the R1441C mutation also impairs dopamine D2 receptor function, as suggested by decreased responses of KI mice in locomotor activity to the inhibitory effect of a D2 receptor agonist, quinpirole. Furthermore, the firing of nigral neurons in R1441C KI mice show reduced sensitivity to suppression induced by quinpirole, dopamine, or AMPH. Together, our data suggest that the R1441C mutation in LRRK2 impairs stimulated dopamine neurotransmission and D2 receptor function, which may represent pathogenic precursors preceding dopaminergic degeneration in PD brains.Parkinson's disease ͉ knockin ͉ dopamine D2 receptor ͉ amphetamine ͉ quinpirole

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mentioning

confidence: 99%

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Tong

Pisani

Martella

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

275

267

View full text Add to dashboard Cite

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“…In the same experiments using kinase-dead mutants, toxicity induced by Lrrk2 was reduced, suggesting that kinase activity may mediate neurodegeneration in vitro [20,57,61]. GTPase-dead mutants also showed decrease toxicity, again lending further support to the intramolecular control of kinase activity by the GTPase-activity domain [57,61].…”

Section: In Vitro Overexpression Of Lrrk2 Causes Neurodegererationmentioning

confidence: 58%

“…A subsequent co-immunoprecipitation study suggested that Lrrk2 (at the COR domain) interacts with parkin (mediated by the RING2 domain) [61]. Additionally, it was reported that aggregates in Lrrk2 transfected cells were increased by expression with parkin and that parkin increases ubiquitination of aggregated Lrrk2 protein, although these findings have yet to be replicated [71].…”

Section: Lrrk2 and The Ubiquitin Proteasomal Degradation Pathwaymentioning

confidence: 91%

Section: In Vitro Overexpression Of Lrrk2 Causes Neurodegererationmentioning

confidence: 99%

“…In HEK293 cells, a small portion of cells transfected with WT and mutant G2019S, Y1699C and R1441C contained Lrrk2 aggregates [61]. In human neuroblastoma SH-SY5Y cell lines and in mouse E15/16 primary cortical cultures, neuronal degeneration was observed in WT cultures; however, degeneration was significantly increased in mutant R1441C, G2019S, Y1699C and was accompanied by apoptosis [61]. In agreement with these findings, the formation of Lrrk2 inclusion bodies and the presence of apoptotic cells was more pronounced in mutants R1441C, G2019S and Y1699C compared with WT in Cos-7 cells [20].…”

Section: In Vitro Overexpression Of Lrrk2 Causes Neurodegererationmentioning

confidence: 99%

See 2 more Smart Citations

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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The Importance of LRRK2 Mutations in Parkinson Disease

Schapira¹

2006

Arch Neurol

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Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration

Cited by 382 publications

References 58 publications

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Update on the Functional Biology of Lrrk2

The Importance of LRRK2 Mutations in Parkinson Disease

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