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The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease.

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Title: The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease.
Authors: Cresto, Noémie (AUTHOR), Gardier, Camille (AUTHOR), Gubinelli, Francesco (AUTHOR), Gaillard, Marie‐Claude (AUTHOR), Liot, Géraldine (AUTHOR), West, Andrew B. (AUTHOR), Brouillet, Emmanuel (AUTHOR)
Source: European Journal of Neuroscience. Feb2019, Vol. 49 Issue 3, p339-363. 25p. 1 Diagram.
Subjects: Parkinson's disease, Brain diseases
Abstract: Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD. LRRK2 and α‐synuclein probably play key roles in Parkinson's disease pathogenesis. In this review, we discuss how these unlikely partners do interact both within neurons that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve regulation of α‐synuclein spreading and neuroinflammation. Understanding the interplay between α‐synuclein and LRRK2 may provide new therapeutic avenues for Parkinson's disease. [ABSTRACT FROM AUTHOR]
Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease.
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  Data: <searchLink fieldCode="AR" term="%22Cresto%2C+Noémie%22">Cresto, Noémie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gardier%2C+Camille%22">Gardier, Camille</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gubinelli%2C+Francesco%22">Gubinelli, Francesco</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gaillard%2C+Marie‐Claude%22">Gaillard, Marie‐Claude</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liot%2C+Géraldine%22">Liot, Géraldine</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22West%2C+Andrew+B%2E%22">West, Andrew B.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Brouillet%2C+Emmanuel%22">Brouillet, Emmanuel</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22European+Journal+of+Neuroscience%22">European Journal of Neuroscience</searchLink>. Feb2019, Vol. 49 Issue 3, p339-363. 25p. 1 Diagram.
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  Data: <searchLink fieldCode="DE" term="%22Parkinson's+disease%22">Parkinson's disease</searchLink><br /><searchLink fieldCode="DE" term="%22Brain+diseases%22">Brain diseases</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD. LRRK2 and α‐synuclein probably play key roles in Parkinson's disease pathogenesis. In this review, we discuss how these unlikely partners do interact both within neurons that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve regulation of α‐synuclein spreading and neuroinflammation. Understanding the interplay between α‐synuclein and LRRK2 may provide new therapeutic avenues for Parkinson's disease. [ABSTRACT FROM AUTHOR]
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  Label:
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  Data: <i>Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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              Text: Feb2019
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