6 results on '"Heaton, George"'
Search Results
2. Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.
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Mamais, Adamantios, Kluss, Jillian H., Bonet-Ponce, Luis, Landeck, Natalie, Langston, Rebekah G., Smith, Nathan, Beilina, Alexandra, Kaganovich, Alice, Ghosh, Manik C., Pellegrini, Laura, Kumaran, Ravindran, Papazoglou, Ioannis, Heaton, George R., Bandopadhyay, Rina, Maio, Nunziata, Kim, Changyoun, LaVoie, Matthew J., Gershlick, David C., and Cookson, Mark R.
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MICROGLIA ,TRANSFERRIN ,LYSOSOMES ,DARDARIN ,PARKINSON'S disease ,GAIN-of-function mutations - Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia. Brain iron deposition is a feature of Parkinson's disease pathology, but how this contributes to neurodegeneration is unclear. This study show that Parkinson's disease-linked mutations in LRRK2 cause aberrant brain iron accumulation in vivo and iron dyshomeostasis in vitro, supporting a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia. [ABSTRACT FROM AUTHOR]
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- 2021
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3. Progress in LRRK2 -Associated Parkinson's Disease Animal Models.
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Seegobin, Steven P., Heaton, George R., Liang, Dongxiao, Choi, Insup, Blanca Ramirez, Marian, Tang, Beisha, and Yue, Zhenyu
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PARKINSON'S disease ,ANIMAL disease models ,DARDARIN ,CAENORHABDITIS elegans - Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). Several genetic manipulations of the LRRK2 gene have been developed in animal models such as rodents, Drosophila , Caenorhabditis elegans , and zebrafish. These models can help us further understand the biological function and derive potential pathological mechanisms for LRRK2. Here we discuss common phenotypic themes found in LRRK2 -associated PD animal models, highlight several issues that should be addressed in future models, and discuss emerging areas to guide their future development. [ABSTRACT FROM AUTHOR]
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- 2020
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4. LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same.
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Berwick, Daniel C., Heaton, George R., Azeggagh, Sonia, and Harvey, Kirsten
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MORPHOLOGY , *DARDARIN , *PARKINSON'S disease , *MICROTUBULES , *CYTOLOGY , *CELL anatomy , *ORGANELLES - Abstract
Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places. [ABSTRACT FROM AUTHOR]
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- 2019
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5. Correction: Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.
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Mamais, Adamantios, Kluss, Jillian H., Bonet-Ponce, Luis, Landeck, Natalie, Langston, Rebekah G., Smith, Nathan, Beilina, Alexandra, Kaganovich, Alice, Ghosh, Manik C., Pellegrini, Laura, Kumaran, Ravindran, Papazoglou, Ioannis, Heaton, George R., Harvey, Kirsten, Bandopadhyay, Rina, Maio, Nunziata, Kim, Changyoun, LaVoie, Matthew J., Gershlick, David C., and Cookson, Mark R.
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IRON ,PARKINSON'S disease ,DARDARIN ,LYSOSOMES ,MICROGLIA ,TRANSFERRIN ,RESEARCH grants - Abstract
Reference 1 Mamais A, Kluss JH, Bonet-Ponce L, Landeck N, Langston RG, Smith N, et al. (2021) Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia. Dr. Kirsten Harvey should be included in the author byline. [Extracted from the article]
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- 2022
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6. Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis.
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Heaton, George R., Landeck, Natalie, Mamais, Adamantios, Nalls, Mike A., Nixon-Abell, Jonathon, Kumaran, Ravindran, Beilina, Alexandra, Pellegrini, Laura, Li, Yan, Harvey, Kirsten, and Cookson, Mark R.
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PARKINSON'S disease , *DARDARIN , *SYNAPTOPHYSIN , *CENTRAL nervous system , *DISEASE risk factors , *SYNAPTIC vesicles - Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are an established cause of inherited Parkinson's disease (PD). LRRK2 is expressed in both neurons and glia in the central nervous system, but its physiological function(s) in each of these cell types is uncertain. Through sequential screens, we report a functional interaction between LRRK2 and Clathrin adaptor protein complex 2 (AP2). Analysis of LRRK2 KO tissue revealed a significant dysregulation of AP2 complex components, suggesting LRRK2 may act upstream of AP2. In line with this hypothesis, expression of LRRK2 was found to modify recruitment and phosphorylation of AP2. Furthermore, expression of LRRK2 containing the R1441C pathogenic mutation resulted in impaired clathrin-mediated endocytosis (CME). A decrease in activity-dependent synaptic vesicle endocytosis was also observed in neurons harboring an endogenous R1441C LRRK2 mutation. Alongside LRRK2, several PD-associated genes intersect with membrane-trafficking pathways. To investigate the genetic association between Clathrin-trafficking and PD, we used polygenetic risk profiling from IPDGC genome wide association studies (GWAS) datasets. Clathrin-dependent endocytosis genes were found to be associated with PD across multiple cohorts, suggesting common variants at these loci represent a cumulative risk factor for disease. Taken together, these findings suggest CME is a LRRK2-mediated, PD relevant pathway. • LRRK2 interacts with components of the clathrin adaptor complex AP2. • LRRK2 KO animals exhibit a significant depletion of AP2 and Clathrin. • The LRRK2-R1441C pathogenic mutation reduces endocytosis in cellular models. • Clathrin-dependent endocytosis genes are associated with Parkinson's disease. [ABSTRACT FROM AUTHOR]
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- 2020
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