GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2

Biosa, Alice; Trančiková, Alžbeta; Civiero, Laura; Glauser, Liliane; Bubacco, Luigi; Greggio, Elisa; Moore, Darren J.

doi:10.1093/hmg/dds522

Cited by 128 publications

(220 citation statements)

References 38 publications

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“…Furthermore, the cross-linking approach allowed the identification of various interdomain contacts, including interactions between distant domains in agreement with previous reports (23). Given the presence of a Roc G-domain and kinase domain in one protein and the similarities of these modules to MAP kinase signaling cascades, it has been hypothesized that an intramolecular regulation mechanism involving these domains must exist for LRRK2 (5,43). On the other hand, by testing direct binding between the G-domain Roc and the kinase domain, previous work demonstrated that these two domains do not bind to each other at high affinity (43).…”

Section: Discussionsupporting

confidence: 85%

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

Guaitoli

Raimondi

Gilsbach

et al. 2016

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

135

156

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Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein containing two catalytic domains: a Ras of complex proteins (Roc) G-domain and a kinase domain. Mutations associated with familial and sporadic Parkinson's disease (PD) have been identified in both catalytic domains, as well as in several of its multiple putative regulatory domains. Several of these mutations have been linked to increased kinase activity. Despite the role of LRRK2 in the pathogenesis of PD, little is known about its overall architecture and how PD-linked mutations alter its function and enzymatic activities. Here, we have modeled the 3D structure of dimeric, full-length LRRK2 by combining domain-based homology models with multiple experimental constraints provided by chemical cross-linking combined with mass spectrometry, negative-stain EM, and small-angle X-ray scattering. Our model reveals dimeric LRRK2 has a compact overall architecture with a tight, multidomain organization. Close contacts between the N-terminal ankyrin and C-terminal WD40 domains, and their proximity-together with the LRR domain-to the kinase domain suggest an intramolecular mechanism for LRRK2 kinase activity regulation. Overall, our studies provide, to our knowledge, the first structural framework for understanding the role of the different domains of full-length LRRK2 in the pathogenesis of PD.LRRK2 | Parkinson's disease | structural modeling | EM | CL-MS

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Section: Discussionsupporting

confidence: 85%

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

Guaitoli

Raimondi

Gilsbach

et al. 2016

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

135

156

View full text Add to dashboard Cite

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“…The R1398 residue is located in the switch II motif of the ROC domain and could be important for the interaction with the γ-phosphate of GTP [87]. Intriguingly, the hypothesis-testing R1398L substitution has increased GTPase activity in vitro [33,110,111]. However, R1398Q does not change GTPase activity of LRRK2, in contrast to expectations [110].…”

Section: Lrrk2 Polymorphisms That May Affect Protein Functionmentioning

confidence: 97%

“…Intriguingly, the hypothesis-testing R1398L substitution has increased GTPase activity in vitro [33,110,111]. However, R1398Q does not change GTPase activity of LRRK2, in contrast to expectations [110]. It would be interesting to check if R1398H LRRK2 has enhanced GTPase activity, as having the opposite effect of R1441C or Y1699C mutations might explain why this is a protective variant.…”

Section: Lrrk2 Polymorphisms That May Affect Protein Functionmentioning

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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“…Furthermore, LRRK2 is expressed in NSCs isolated from both the DG and SVZ of E18.5 mice. The LRRK2 protein may interact with the regulator of neurite outgrowth during embryonic neurogenesis, CRMP2 [77] and numerous studies have demonstrated that mutant LRRK2 overexpression decreases neurite length/outgrowth, while LRRK2 deficits result in an increase of neurite length and arborization [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94]. Moreover, LRRK2 has been shown to bind Wnt signaling components (the DVL proteins) and play a role in the canonical Wnt/bcatenin signaling pathway, an important pathway for neurogenesis and in particular the development of DA neurons [83,95,96].…”

Section: Evidence For a Developmental Component Of Pd: Deregulated Emmentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2

Cited by 128 publications

References 38 publications

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

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

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

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