Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

Nguyen, An Phu Tran; Moore, Darren J.

doi:10.1007/978-3-319-49969-7_4

Cited by 51 publications

(70 citation statements)

References 75 publications

(177 reference statements)

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“…It has been debated as to whether the LRRK2 GTPase domain can form a dimer and whether dimerization has a key role in regulating GTPase activity. Currently, the LRRK2 GTPase domain is thought to function in an active monomeric form regardless of its original conformation in solution, to include cases where both monomeric and dimeric conformations are present, due to its nucleotide‐dependent states (14, 17, 23). However, how the dimeric or monomeric states affect GTPase activity remains unclear.…”

Section: Discussionmentioning

confidence: 99%

The Parkinson's disease–associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2

Huang

Park

et al. 2018

FASEB j.

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Parkinson disease–associated mutations within the GTPase domain Ras of complex proteins (ROC) of leucine rich repeat kinase 2 (LRRK2) result in an abnormal over‐activation of its kinase domain. However, the mechanisms involved remain unclear. Recent study has shown that LRRK2 G‐domain cycles between monomeric and dimeric conformations upon binding to GTP or guanosine diphosphate, and that the Parkinson's disease (PD)‐associated R1441C/G/H mutations impair the G‐domain monomer‐dimer dynamics and trap the G‐domain in a constitutive monomeric conformation. That led us to question whether other disease‐associated mutations in G‐domain would also affect its conformation. Here, we report that another PD‐associated N1437H mutation also impairs its monomer‐dimer conformational dynamics and GTPase activity. In contrast with mutations at R1441, ROCN1437H was found to be locked in a stable dimeric conformation in solution and its GTPase activity was ∼4‐fold lower than that of the wild‐type. Furthermore, the N1437H mutation reduced the GTP binding affinity by ∼2.5‐fold when compared with other pathogenic G‐domain mutations. Moreover, ROCN1437h was found to have a slower GTP dissociation rate, indicating that N1437H might interrupt the nucleotide exchange cycle. Taken together, our data support that conformational dynamics is important for LRRK2 GTPase activity and that the N1437H mutation impairs GTPase activity by locking the ROC domain in a persistently dimeric state.—Huang, X., Wu, C., Park, Y., Long, X., Hoang, Q. Q., Liao, J. The Parkinson's disease‐associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2. FASEB J. 33, 4814–4823 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

The Parkinson's disease–associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2

Huang

Park

et al. 2018

FASEB j.

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“…LRRK2 can function as both a GTPase and kinase in vitro and in cells, with an intact GTPase domain and the capacity for GTP-binding being critically required for kinase activity (13)(14)(15)(16). Familial PD-linked mutations in LRRK2 commonly increase its kinase activity in mammalian cells to varying degrees and promote substrate phosphorylation (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…at Ser1292) (17)(18)(19). For the common G2019S mutation located within the kinase activation loop, the effect on kinase activity is direct, whereas Roc-COR domain mutations are considered to act indirectly by impairing GTP hydrolysis activity and thereby prolonging the GTP-bound 'on' state of LRRK2 (15,(20)(21)(22)(23)(24). While GTPase and kinase activities of LRRK2 are clearly altered by familial mutations, it is less clear whether or how these enzymatic activities contribute to neuronal toxicity induced by mutant LRRK2.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

Nguyen

Tsika

Kelly

et al. 2019

Preprint

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and represent the most common known cause of PD. LRRK2 can function as both a protein kinase and GTPase and PDlinked mutations are known to influence both of these enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage and toxicity in cellular models, the mechanisms underlying these pathogenic effects remain uncertain.Rodent models based upon familial LRRK2 mutations often lack the hallmark features of PD and robust neurodegenerative phenotypes in general. Here, we develop a robust pre-clinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of full-length human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or in-diet dosing with the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the selective and robust destabilization of human LRRK2 protein in the rat brain relative to endogenous LRRK2. Our study further demonstrates that dopaminergic neurodegeneration induced by G2019S LRRK2 critically requires normal GTPase activity. The introduction of hypothesis-testing mutations that increase GTP hydrolysis or impair GTP binding activity provide neuroprotection against G2019S LRRK2 via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

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“…Histone deacetylase 6 (HDAC6) plays a key role in aggresome formation. HDAC6 is a member of a family of HDACs containing 11 Zn 2+ -dependent enzymes (HDAC1-11) and 7 NAD + -dependent proteins (Sirtuin1-7) that are subdivided into 4 classes, Class I (HDAC1, 2, 3, and 8), Class IIa (HDAC4, 5, and 7) and IIb (HDAC6 and 10), Class III (Sirtuin1-7), and Class IV (HDAC11). HDAC6 stands out among the other HDACs because it is predominantly cytosolic, contains two catalytic domains and has a ubiquitin binding domain.…”

mentioning

confidence: 99%

“…Mutations in the Roc and COR domain diminish the GTPase activity of LRRK2, whereas mutations in the kinase domain enhance its kinase activity. It is generally assumed that kinase hyperactivity is linked to neurotoxicity, but it is less clear how diminished LRRK2 GTPase activity contributes to disease 7 .…”

mentioning

confidence: 99%

LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation

Lucas

Bauer

Chinnaiya

et al. 2019

Preprint

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Mutations in LRRK2 are the most common cause of dominantly inherited Parkinson's disease (PD). A proportion of LRRK2 PD exhibits Lewy pathology with accumulations of α-synuclein and ubiquitin in intracellular aggregates that are indistinguishable from idiopathic PD. LRRK2 is a multi-domain protein with both GTPase and kinase activities that has been shown to affect various cellular processes including protein

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Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

Cited by 51 publications

References 75 publications

The Parkinson's disease–associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2

The Parkinson's disease–associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2

Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation

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