Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues

Iannotta, Lucia; Biosa, Alice; Kluss, Jillian H.; Tombesi, Giulia; Kaganovich, Alice; Cogo, Susanna; Plotegher, Nicoletta; Civiero, Laura; Lobbestael, Evy; Baekelandt, Veerle; Cookson, Mark; Greggio, Elisa

doi:10.3390/cells9112344

Cited by 42 publications

(47 citation statements)

References 56 publications

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“…Interestingly, in neutrophils from carriers of the less common R1441G mutation in LRRK2, a significant increase in pT73-Rab10 is detected in comparison to healthy controls, irrespective of disease status 12 . This is consistent with findings reported in transgenic mice expressing R1441C or G2019S, where a robust increase in Rab10 phosphorylation was observed in R14411C but not G2019S mice 13 . Most recently, using a proprietary antibody raised against pT73-Rab10, Wang and colleagues reported that phosphorylated Rab10 levels, normalized to total LRRK2, are increased in PBMCs of affected carriers of the G2019S mutation 8 and are reduced in cells treated ex vivo with LRRK2 kinase inhibitors.…”

supporting

confidence: 93%

Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts

Peptropoulou-Vathi¹,

Simitsi

Valkimadi³

et al. 2021

Preprint

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Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates (e.g. Rab10 or other Rab GTPases). We have previously shown that intrinsic kinase activity of LRRK2 isolated from PBMCs of G2019S carriers is elevated, irrespective of disease status. In the present study we find that phosphorylation of Rab10 is also elevated in G2019S carriers, but only those with PD. Additionally, phosphorylation of this substrate is also elevated in 2 separate idiopathic PD cohorts, but not in carriers of the A53T mutation in α-synuclein. In contrast, Rab29 phosphorylation was specifically reduced in urinary exosomes from A53T and idiopathic PD patients. Taken together, our findings highlight the need for the assessment of multiple complimentary targets for a more comprehensive picture of the disease.

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supporting

confidence: 93%

Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts

Peptropoulou-Vathi¹,

Simitsi

Valkimadi³

et al. 2021

Preprint

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“…For example, G2019S and I2020T, both located at the kinase domain, increase the phosphorylation activity of LRRK2 137,138 , most likely through the stabilization of its active status 139 . Alternatively, mutations at the ROC-COR domain have a direct effect on ROC by slowing GTP hydrolysis, which affects cellular phosphorylation of LRRK2 substrates by impairing LRRK2 recruitment to signaling compartments or by improper interactions with ROC binding partners 132,[140][141][142][143] .…”

Section: -3-3 Roles In Parkinson's Diseasementioning

confidence: 99%

Pathways to Parkinson’s disease: a spotlight on 14-3-3 proteins

Giusto

Yacoubian

Greggio

et al. 2021

npj Parkinsons Dis.

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Abstract14-3-3s represent a family of highly conserved 30 kDa acidic proteins. 14-3-3s recognize and bind specific phospho-sequences on client partners and operate as molecular hubs to regulate their activity, localization, folding, degradation, and protein–protein interactions. 14-3-3s are also associated with the pathogenesis of several diseases, among which Parkinson’s disease (PD). 14-3-3s are found within Lewy bodies (LBs) in PD patients, and their neuroprotective effects have been demonstrated in several animal models of PD. Notably, 14-3-3s interact with some of the major proteins known to be involved in the pathogenesis of PD. Here we first provide a detailed overview of the molecular composition and structural features of 14-3-3s, laying significant emphasis on their peculiar target-binding mechanisms. We then briefly describe the implication of 14-3-3s in the central nervous system and focus on their interaction with LRRK2, α-Synuclein, and Parkin, three of the major players in PD onset and progression. We finally discuss how different types of small molecules may interfere with 14-3-3s interactome, thus representing a valid strategy in the future of drug discovery.

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“…Our study suggests absence of astrocyte degeneration or atrophy, since the levels of the cytosolic astrocyte marker GS were not perturbed in the context of disease. Accordingly, the presence of astrocyte reactivity has been reported in different transgenic mice overexpressing the LRRK2 G2019S kinase [34, 91].…”

Section: Discussionmentioning

confidence: 99%

Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease

Iovino

Giusti

Pischedda

et al. 2021

Preprint

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The Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80% of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinson's disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In Lrrk2 G2019S knockin mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane, causing its intracellular relocalization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD.

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Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues

Cited by 42 publications

References 56 publications

Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts

Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts

Pathways to Parkinson’s disease: a spotlight on 14-3-3 proteins

Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease

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