Neurodegeneration caused by LRRK2-G2019S requires Rab10 in select dopaminergic neurons

Petridi, Stavroula; Middleton, C. A.; Fellgett, Alison; Covill, Laura; Stewart, Amy Stieler; Munns, Jack; Kohrs, Friederike Elisabeth; Hiesinger, P. Robin; Wilson, Laurence G.; Chawla, Sangeeta; Elliott, Christopher J.H.

doi:10.1101/586073

Cited by 3 publications

(2 citation statements)

References 66 publications

(84 reference statements)

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“…Rab10 is a well-known substrate of LRRK2, and in vitro assays suggested that PD-related neurodegeneration may start by LRRK2 -G2019S increasing phosphorylation of Rab10 70 . It is also known that Rab10 is involved in LRRK2 and other Rabs relocalization 71 .…”

Section: Resultsmentioning

confidence: 99%

Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define diagnostic biosignatures for Parkinson’s Disease

Hadisurya

Kuwaranancharoen

et al. 2022

Preprint

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been recognized as genetic risk factors for both familial and sporadic forms of Parkinson's disease (PD). However, compared to cancer, overall lower genetic mutations contribute to the cause of PD, propelling the search for protein biomarkers for early detection of the disease. Utilizing 141 urine samples from four groups, healthy individuals (control), healthy individuals with G2019S mutation in the LRRK2 gene (non-manifesting carrier/NMC), PD individuals without G2019S mutation (idiopathic PD/iPD), and PD individuals with G2019S mutation (LRRK2 PD), we applied a proteomics strategy to determine potential diagnostic and prognostic biomarkers for PD from urinary extracellular vesicles (EVs). After efficient isolation of urinary EVs through chemical affinity followed by mass spectrometric analyses of EV peptides and enriched phosphopeptides, we identified and quantified 4,480 unique proteins and 2,682 unique phosphoproteins. We detected multiple proteins and phosphoproteins elevated in PD EVs that are known to be involved in important PD pathways such as neuronal cell death, neuroinflammation, autophagy, and formation of amyloid fibrils. We established two panels of proteins and phosphoproteins as novel candidates for disease and risk biomarkers, and substantiated using ROC, machine learning, and in-depth network analysis. Several disease biomarkers were further validated in patients with PD using parallel reaction monitoring (PRM) and immunoassay for targeted quantitation. These findings demonstrate a general strategy of utilizing biofluid EV proteome/phosphoproteome as an outstanding and non-invasive source for a wide range of disease exploration.

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Section: Resultsmentioning

confidence: 99%

Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define diagnostic biosignatures for Parkinson’s Disease

Hadisurya

Kuwaranancharoen

et al. 2022

Preprint

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“…Rab10 is thus crucial for the early steps of embryogenesis, although the exact mechanism controlled by Rab10 during embryogenesis remains to be defined. Surprisingly, in Drosophila, a null Rab10 allele is viable [64].…”

Section: Rab10mentioning

confidence: 99%

Rabs in Signaling and Embryonic Development

Nassari

Olmo

Jean

2020

IJMS

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Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo.

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Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define putative diagnostic biosignatures for Parkinson’s disease

Hadisurya

Kuwaranancharoen

et al. 2023

Commun Med

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Background Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been recognized as genetic risk factors for Parkinson’s disease (PD). However, compared to cancer, fewer genetic mutations contribute to the cause of PD, propelling the search for protein biomarkers for early detection of the disease. Methods Utilizing 138 urine samples from four groups, healthy individuals (control), healthy individuals with G2019S mutation in the LRRK2 gene (non-manifesting carrier/NMC), PD individuals without G2019S mutation (idiopathic PD/iPD), and PD individuals with G2019S mutation (LRRK2 PD), we applied a proteomics strategy to determine potential diagnostic biomarkers for PD from urinary extracellular vesicles (EVs). Results After efficient isolation of urinary EVs through chemical affinity followed by mass spectrometric analyses of EV peptides and enriched phosphopeptides, we identify and quantify 4476 unique proteins and 2680 unique phosphoproteins. We detect multiple proteins and phosphoproteins elevated in PD EVs that are known to be involved in important PD pathways, in particular the autophagy pathway, as well as neuronal cell death, neuroinflammation, and formation of amyloid fibrils. We establish a panel of proteins and phosphoproteins as novel candidates for disease biomarkers and substantiate the biomarkers using machine learning, ROC, clinical correlation, and in-depth network analysis. Several putative disease biomarkers are further partially validated in patients with PD using parallel reaction monitoring (PRM) and immunoassay for targeted quantitation. Conclusions These findings demonstrate a general strategy of utilizing biofluid EV proteome/phosphoproteome as an outstanding and non-invasive source for a wide range of disease exploration.

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Neurodegeneration caused by LRRK2-G2019S requires Rab10 in select dopaminergic neurons

Abstract: Acknowledgements. We are grateful for the gifts of flies from Kristin Scott,

Cited by 3 publications

References 66 publications

Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define diagnostic biosignatures for Parkinson’s Disease

Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define diagnostic biosignatures for Parkinson’s Disease

Rabs in Signaling and Embryonic Development

Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define putative diagnostic biosignatures for Parkinson’s disease

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