LRRK2 dephosphorylation increases its ubiquitination

Zhao, Jingquan; Molitor, Tyler P.; Langston, J. William; Nichols, R. Jeremy

doi:10.1042/bj20141305

Cited by 64 publications

(106 citation statements)

References 72 publications

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“…Whether this is strictly due to a loss of phosphorylation by LRRK2 of one (or more) substrates remains to be definitively established, as inhibition of LRRK2 kinase activity, either genetically or pharmacologically, can also alter both the stability and localization of the protein [13,30], and perhaps thus its ability to induce neuronal death. This phenomenon appears to be linked to de-phosphorylation of LRRK2 itself, which is accompanied by increased K63 and K48 ubiquitination and degradation [21,31]. In should be noted however, that in primary neurons treated with MLi-2, we did not observe, at a qualitative level by immunofluorescence, a dramatic reduction in the levels of over-expressed WT or mutant LRRK2.…”

Section: Discussionmentioning

confidence: 85%

Activation of FADD-Dependent Neuronal Death Pathways as a Predictor of Pathogenicity for LRRK2 Mutations

et al. 2016

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BackgroundDespite the plethora of sequence variants in LRRK2, only a few clearly segregate with PD. Even within this group of pathogenic mutations, the phenotypic profile can differ widely.ObjectiveWe examined multiple properties of LRRK2 behavior in cellular models over-expressing three sequence variants described in Greek PD patients in comparison to several known pathogenic and non-pathogenic LRRK2 mutations, to determine if specific phenotypes associated with pathogenic LRRK2 can be observed in other less-common sequence variants for which pathogenicity is unclear based on clinical and/or genetic data alone.MethodsThe oligomerization, activity, phosphorylation, and interaction with FADD was assessed in HEK293T cells over-expressing LRRK2; while the induction of neuronal death was determined by quantifying apoptotic nuclei in primary neurons transiently expressing LRRK2.ResultsOne LRRK2 variant, A211V, exhibited a modest increase in kinase activity, whereas only the pathogenic mutants G2019S and I2020T displayed significantly altered auto-phosphorylation. We observed an induction of detergent-insoluble high molecular weight structures upon expression of pathogenic LRRK2 mutants, but not the other LRRK2 variants. In contrast, each of the variants tested induced apoptotic death of cultured neurons similar to pathogenic LRRK2 in a FADD-dependent manner.ConclusionsOverall, despite differences in some properties of LRRK2 function such as kinase activity and its oligomerization, each of the LRRK2 variants examined induced neuronal death to a similar extent. Furthermore, our findings further strengthen the notion of a convergence on the extrinsic cell death pathway common to mutations in LRRK2 that are capable of inducing neuronal death.

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Section: Discussionmentioning

confidence: 85%

Activation of FADD-Dependent Neuronal Death Pathways as a Predictor of Pathogenicity for LRRK2 Mutations

et al. 2016

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“…and threonines interact with 14-3-3, for example LRRK2, p53, and BAD (30,(33)(34)(35)(36). However, the CFTR R-domain interaction with 14-3-3 is exceptional for the large number of interaction sites (nine).…”

Section: Discussionmentioning

confidence: 99%

Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR

Stevers

Lam

Leysen

et al. 2016

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

128

140

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Cystic fibrosis is a fatal genetic disease, most frequently caused by the retention of the CFTR (cystic fibrosis transmembrane conductance regulator) mutant protein in the endoplasmic reticulum (ER). The binding of the 14-3-3 protein to the CFTR regulatory (R) domain has been found to enhance CFTR trafficking to the plasma membrane. To define the mechanism of action of this protein–protein interaction, we have examined the interaction in vitro. The disordered multiphosphorylated R domain contains nine different 14-3-3 binding motifs. Furthermore, the 14-3-3 protein forms a dimer containing two amphipathic grooves that can potentially bind these phosphorylated motifs. This results in a number of possible binding mechanisms between these two proteins. Using multiple biochemical assays and crystal structures, we show that the interaction between them is governed by two binding sites: The key binding site of CFTR (pS768) occupies one groove of the 14-3-3 dimer, and a weaker, secondary binding site occupies the other binding groove. We show that fusicoccin-A, a natural-product tool compound used in studies of 14-3-3 biology, can stabilize the interaction between 14-3-3 and CFTR by selectively interacting with a secondary binding motif of CFTR (pS753). The stabilization of this interaction stimulates the trafficking of mutant CFTR to the plasma membrane. This definition of the druggability of the 14-3-3–CFTR interface might offer an approach for cystic fibrosis therapeutics.

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“…Studies have shown that constitutive phosphorylation regulates the subcellular localization, stability, and function of LRRK2 [101]. Mutations in the KIN and ROCO domains alter constitutive phosphorylation of LRRK2 and are associated with PD pathogenesis [102]. The G2019S mutation of LRRK2 increased phosphorylation in dopaminergic cell lines, resulting in abnormal neurite growth and increased neuronal vulnerability [103].…”

Section: Lrrk2mentioning

confidence: 99%

“…LRRK2 ubiquitination occurs at multiple N-terminal ARM lysine (K) residues of LRRK2 (K27, K29, K48, K63) [100]. Ubiquitination at K48 and K63 residues signal the degradation of LRRK2 by ubiquitin-proteasome and autophagy-lysosome pathways, respectively [100, 102]. …”

Section: Lrrk2mentioning

confidence: 99%

“…Additionally, PD-associated LRRK2 mutations such as R1441C, R1441G, Y1699C and I2020T decreased constitutive phosphorylation of LRRK2 in vitro , resulting in its hyperubiquitination and instability [115]. These unstable mutants formed abnormal protein complexes [102] and promoted cytosolic aggregation of LRRK2 [115] as compared to the WT. Knockdown of LRRK2 impaired autophagy-lysosomal degradation in transgenic mice, resulting in increased protein ubiquitination, oxidative stress, inflammation and apoptosis [34].…”

Section: Lrrk2mentioning

confidence: 99%

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The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Pajarillo

Rizor

Lee

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD), and the most prevalent movement disorder. PD is characterized by dopaminergic neurodegeneration in the substantia nigra, but its etiology has yet to be established. Among several genetic variants contributing to PD pathogenesis, α-synuclein and leucine-rich repeat kinase (LRRK2) are widely associated with neuropathological phenotypes in familial and sporadic PD. α-Synuclein and LRRK2 found in Lewy bodies, a pathogenetic hallmark of PD, are often posttranslationally modified. As posttranslational modifications (PTMs) are key processes in regulating the stability, localization, and function of proteins, PTMs have emerged as important modulators of pathogenic mechanisms of α-synuclein and LRRK2. Aberrant PTMs altering phosphorylation, ubiquitination, nitration and truncation of these proteins promote PD pathogenesis, while other PTMs such as sumoylation may be protective. Although the causes of many aberrant PTMs are unknown, environmental risk factors may contribute to their aberrancy. Environmental toxicants such as rotenone and paraquat have been shown to interact with these proteins and promote their abnormal PTMs. Notably, manganese (Mn) exposure leads to PD-like neurological disorder referred to as manganism—and induces pathogenic PTMs of α-synuclein and LRRK2. In this review, we highlight the role of PTMs of LRRK2 and α-synuclein in PD pathogenesis and discuss the impact of environmental risk factors on their aberrancy.

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LRRK2 dephosphorylation increases its ubiquitination

Cited by 64 publications

References 72 publications

Activation of FADD-Dependent Neuronal Death Pathways as a Predictor of Pathogenicity for LRRK2 Mutations

Activation of FADD-Dependent Neuronal Death Pathways as a Predictor of Pathogenicity for LRRK2 Mutations

Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

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