Kinase activity of mutant LRRK2 mediates neuronal toxicity

2006 ◽  
Vol 9 (10) ◽  
pp. 1231-1233 ◽  
Author(s):  
Wanli W Smith ◽  
Zhong Pei ◽  
Haibing Jiang ◽  
Valina L Dawson ◽  
Ted M Dawson ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Neuronal Toxicity ◽  
Mutant Lrrk2

Kinase activity is required for the toxic effects of mutant LRRK2/dardarin

2006 ◽  
Vol 23 (2) ◽  
pp. 329-341 ◽  
Author(s):  
Elisa Greggio ◽  
Shushant Jain ◽  
Ann Kingsbury ◽  
Rina Bandopadhyay ◽  
Patrick Lewis ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Toxic Effects ◽  
Mutant Lrrk2

scholarly journals 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening

2015 ◽  
Vol 25 (1) ◽  
pp. 109-122 ◽  
Author(s):  
Nicholas J. Lavalley ◽  
Sunny R. Slone ◽  
Huiping Ding ◽  
Andrew B. West ◽  
Talene A. Yacoubian
Keyword(s):  
Kinase Activity ◽  
Mutant Lrrk2 ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Kinase activity of mutant LRRK2 manifests differently in hetero-dimeric vs. homo-dimeric complexes

2019 ◽  
Vol 476 (3) ◽  
pp. 559-579 ◽  
Author(s):  
Emmanouela Leandrou ◽  
Eliana Markidi ◽  
Anna Memou ◽  
Katerina Melachroinou ◽  
Elisa Greggio ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Cultured Cells ◽  
Kinase Domain ◽  
Small Gtpase ◽  
Wild Type ◽  
Risk Variant ◽  
Dimeric Complexes ◽  
Mutant Lrrk2 ◽  
Mutant Forms

Abstract The Parkinson's disease (PD) protein leucine-rich repeat kinase 2 (LRRK2) exists as a mixture of monomeric and dimeric species, with its kinase activity highly concentrated in the dimeric conformation of the enzyme. We have adapted the proximity biotinylation approach to study the formation and activity of LRRK2 dimers isolated from cultured cells. We find that the R1441C and I2020T mutations both enhance the rate of dimer formation, whereas, the G2019S kinase domain mutant is similar to WT, and the G2385R risk factor variant de-stabilizes dimers. Interestingly, we find a marked departure in the kinase activity between G2019S–LRRK2 homo-dimers and wild-type-G2019S hetero-dimers. While the homo-dimeric G2019S–LRRK2 exhibits the typical robust enhancement of kinase activity, hetero-dimers comprised of wild-type (WT) and G2019S–LRRK2 exhibit kinase activity similar to WT. Dimeric complexes of specific mutant forms of LRRK2 show reduced stability following an in vitro kinase reaction, in LRRK2 mutants for which the kinase activity is similar to WT. Phosphorylation of the small GTPase Rab10 follows a similar pattern in which hetero-dimers of WT and mutant LRRK2 show similar levels of phosphorylation of Rab10 to WT homo-dimers; while the levels of pRab10 are significantly increased in cells expressing mutant homo-dimers. Interestingly, while the risk variant G2385R leads to a de-stabilization of LRRK2 dimers, those dimers possess significantly elevated kinase activity. The vast majority of familial LRRK2-dependent PD cases are heterozygous; thus, these findings raise the possibility that a crucial factor in disease pathogenesis may be the accumulation of homo-dimeric mutant LRRK2.

scholarly journals LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel Ysselstein ◽  
Maria Nguyen ◽  
Tiffany J. Young ◽  
Alex Severino ◽  
Michael Schwake ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Kinase Activity ◽  
Alpha Synuclein ◽  
Negative Regulator ◽  
Mutant Lrrk2 ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

AbstractMutations in LRRK2 and GBA1 are common genetic risk factors for Parkinson’s disease (PD) and major efforts are underway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase). Here we describe a mechanistic and therapeutic convergence of LRRK2 and GCase in neurons derived from patients with PD. We find that GCase activity was reduced in dopaminergic (DA) neurons derived from PD patients with LRRK2 mutations. Inhibition of LRRK2 kinase activity results in increased GCase activity in DA neurons with either LRRK2 or GBA1 mutations. This increase is sufficient to partially rescue accumulation of oxidized dopamine and alpha-synuclein in PD patient neurons. We have identified the LRRK2 substrate Rab10 as a key mediator of LRRK2 regulation of GCase activity. Together, these results suggest an important role of mutant LRRK2 as a negative regulator of lysosomal GCase activity.

scholarly journals Mutant LRRK2 Toxicity in Neurons Depends on LRRK2 Levels and Synuclein But Not Kinase Activity or Inclusion Bodies

2014 ◽  
Vol 34 (2) ◽  
pp. 418-433 ◽  
Author(s):  
G. Skibinski ◽  
K. Nakamura ◽  
M. R. Cookson ◽  
S. Finkbeiner
Keyword(s):  
Inclusion Bodies ◽  
Kinase Activity ◽  
Mutant Lrrk2

scholarly journals LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease

2018 ◽  
Vol 115 (21) ◽  
pp. 5576-5581 ◽  
Author(s):  
Maria Nguyen ◽  
Dimitri Krainc
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Vesicle ◽  
Dopaminergic Neurons ◽  
Kinase Activity ◽  
Dopamine Metabolism ◽  
Synaptic Dysfunction ◽  
Leucine Rich Repeat ◽  
Mutant Lrrk2 ◽  
Activity Dependent

Recently identified Parkinson’s disease (PD) genes involved in synaptic vesicle endocytosis, such as DNAJC6 (auxilin), have further implicated synaptic dysfunction in PD pathogenesis. However, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential clathrin binding, resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons. Moreover, impaired synaptic vesicle endocytosis contributed to the accumulation of oxidized dopamine that in turn mediated pathogenic effects such as decreased glucocerebrosidase activity and increased α-synuclein in mutant LRRK2 neurons. Importantly, these pathogenic phenotypes were partially attenuated by restoring auxilin function in mutant LRRK2 dopaminergic neurons. Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis, leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons.

scholarly journals The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

2020 ◽  
Author(s):  
Adrienne E. D. Stormo ◽  
Molly FitzGibbon ◽  
Farbod Shavarebi ◽  
Elizabeth M. Earley ◽  
Lotus S. Lum ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Kinase Activity ◽  
Missense Mutations ◽  
Quantitative Mass Spectrometry ◽  
Lrrk2 G2019s ◽  
Mutant Lrrk2 ◽  
Lrrk2 Kinase ◽  
Regulatory Loop ◽  
Familial Parkinson’S Disease ◽  
Lrrk2 Kinase Activity

AbstractMissense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s Disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (Tripartite Motif Family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2822-982, a flexible interdomain region we designate the “Regulatory Loop” (RL). Phosphorylation of LRRK2 Ser910/935 within LRRK2 RL serves as a molecular switch controlling LRRK2’s association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 prevents upregulation of LRRK2 kinase activity by Rab29 and also rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, modulating its cytoskeletal recruitment, turnover, kinase activity, and cytotoxicity.

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