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Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

BACKGROUND: Inherited mutations in the LRRK2 protein are common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) su...

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Autores principales: Fellgett, Alison, Middleton, C. Adam, Munns, Jack, Ugbode, Chris, Jaciuch, David, Wilson, Laurence G., Chawla, Sangeeta, Elliott, Christopher J.H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609683/
https://www.ncbi.nlm.nih.gov/pubmed/34250948
http://dx.doi.org/10.3233/JPD-202421
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author Fellgett, Alison
Middleton, C. Adam
Munns, Jack
Ugbode, Chris
Jaciuch, David
Wilson, Laurence G.
Chawla, Sangeeta
Elliott, Christopher J.H.
author_facet Fellgett, Alison
Middleton, C. Adam
Munns, Jack
Ugbode, Chris
Jaciuch, David
Wilson, Laurence G.
Chawla, Sangeeta
Elliott, Christopher J.H.
author_sort Fellgett, Alison
collection PubMed
description BACKGROUND: Inherited mutations in the LRRK2 protein are common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. OBJECTIVE: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. METHODS: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. RESULTS: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. CONCLUSION: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.
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spelling pubmed-86096832021-12-10 Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons Fellgett, Alison Middleton, C. Adam Munns, Jack Ugbode, Chris Jaciuch, David Wilson, Laurence G. Chawla, Sangeeta Elliott, Christopher J.H. J Parkinsons Dis Research Report BACKGROUND: Inherited mutations in the LRRK2 protein are common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. OBJECTIVE: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. METHODS: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. RESULTS: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. CONCLUSION: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease. IOS Press 2021-10-12 /pmc/articles/PMC8609683/ /pubmed/34250948 http://dx.doi.org/10.3233/JPD-202421 Text en © 2021 – The authors. Published by IOS Press https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Report
Fellgett, Alison
Middleton, C. Adam
Munns, Jack
Ugbode, Chris
Jaciuch, David
Wilson, Laurence G.
Chawla, Sangeeta
Elliott, Christopher J.H.
Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons
title Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons
title_full Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons
title_fullStr Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons
title_full_unstemmed Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons
title_short Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons
title_sort multiple pathways of lrrk2-g2019s/rab10 interaction in dopaminergic neurons
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609683/
https://www.ncbi.nlm.nih.gov/pubmed/34250948
http://dx.doi.org/10.3233/JPD-202421
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