The unlikely partnership between LRRK2 and α-synuclein in Parkinson's disease.
Parkinson
aggregation
autophagy
mitochondria
mitophagy
neurodegeneration
neuroinflammation
prion-like propagation
Journal
The European journal of neuroscience
ISSN: 1460-9568
Titre abrégé: Eur J Neurosci
Pays: France
ID NLM: 8918110
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
13
05
2018
revised:
11
09
2018
accepted:
17
09
2018
pubmed:
1
10
2018
medline:
18
6
2020
entrez:
1
10
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30269383
doi: 10.1111/ejn.14182
pmc: PMC6391223
mid: NIHMS990755
doi:
Substances chimiques
alpha-Synuclein
0
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
339-363Subventions
Organisme : "Fondation de France, Parkinson committee"
ID : AAP 2014, Engt 2014-0052580
Pays : International
Organisme : NINDS NIH HHS
ID : R01 NS064934
Pays : United States
Organisme : European Union Horizon 2020 Programme
ID : H2020-MSCA-ITN-2015
Pays : International
Organisme : Marie Skłodowska-Curie Innovative Training Network
ID : 676408
Pays : International
Organisme : NINDS NIH HHS
ID : U01 NS097028
Pays : United States
Organisme : "Fondation de France, Parkinson committee"
ID : AAP 2010, Engt 00016819
Pays : International
Organisme : NeurATRIS, "Investissement d'Avenir"
ID : ANR-11-INBS-0011
Pays : International
Organisme : NINDS NIH HHS
ID : R33 NS097643
Pays : United States
Organisme : NIH HHS
ID : R01 NS064934
Pays : United States
Organisme : NIH HHS
ID : R33 NS097643
Pays : United States
Organisme : NIH HHS
ID : U01 NS097028
Pays : United States
Informations de copyright
© 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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