<i>LRRK2</i>G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β

Lin, Chin‐Hsien; Tsai, Pei-I; Wu, Ruey‐Meei; Chien, Ching‐Te

doi:10.1523/jneurosci.1737-10.2010

Cited by 156 publications

(218 citation statements)

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“…[53][54][55] Other studies have provided evidence supporting the direct activation of GSK-3β through physical interactions with mutant forms of LRRK-2, a gene commonly associated with increased risk of developing familial associated PD. 25,26 The aforementioned studies combined with our current results suggest that hyperactivation of GSK-3β may be the primary mechanism by which this protein is linked to PD (Figure 7). Indeed, a growing body of evidence from our laboratory and others define the important roles, kinases, such as GSK-3β, CK2, PLK2 and 3, and GRK1-5 have in the development and pathology of PD through the phosphorylation of α-Syn and Tau 16,[18][19][20][21][22][23][24][53][54][55][56][57] (Supplementary Table S3 and associated references).…”

Section: Discussionmentioning

confidence: 54%

“…Yet several studies have provided evidence that leucine-rich repeat kinase-2 (LRRK2), a kinase, that when mutated is involved in familial forms of PD, can directly interact with, and activate GSK-3β, resulting in increased p-TAU formation. 25,26 Among the kinases known to hyperphosphorylate Tau, glycogen synthase kinase-3β (GSK-3β) may be the most important given its ability to phosphorylate Tau at the majority of its serine/threonine sites that cause associated toxicities in AD. 27,28 The importance of GSK-3β is illustrated in that it is embryonically lethal when knocked out in mice.…”

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confidence: 99%

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GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

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Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson's disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.

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Section: Discussionmentioning

confidence: 54%

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confidence: 99%

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

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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%

“…Moreover, it has been demonstrated that pathogenic mutations of LRRK2 modulate its interaction with different Wnt pathway molecules, including DVL and GSK3, a component of the b-catenin destruction complex [83,95]. Importantly, KD of LRRK2 results in enhanced canonical Wnt signaling [96].…”

Section: Lrrk2 Is Involved In Wnt Signalingmentioning

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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“…Transgenic expression of human G2019S LRRK2 in Drosophila causes dendrite degeneration and dopaminergic (DA) neurons loss followed by locomotor dysfunction [114,115]. Importantly, this effect was diminished by pharmacological inhibition of kinase activity of G2019S mutant or by overexpression of parkin, a protein implicated in autosomalrecessive Parkinsonism [116,117].…”

Section: Direct Toxic Effects Of Lrrk2 Expression In Neuronsmentioning

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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LRRK2G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β

Cited by 156 publications

References 65 publications

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

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

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

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