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

• Published in: The European journal of neuroscience Vol. 49; no. 3; pp. 339 - 363
• Main Authors: Cresto, Noémie, Gardier, Camille, Gubinelli, Francesco, Gaillard, Marie‐Claude, Liot, Géraldine, West, Andrew B., Brouillet, Emmanuel
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.02.2019; Wiley
• Subjects: aggregation; alpha-Synuclein - adverse effects; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; autophagy; Brain - metabolism; Human health and pathology; Humans; Inflammation; Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - adverse effects; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; Life Sciences; LRRK2 protein; mitochondria; mitophagy; Movement disorders; Mutation; Nerve Degeneration - metabolism; Neurodegeneration; Neurodegenerative diseases; neuroinflammation; Neurons - metabolism; Neurons and Cognition; Neurotoxicity; Parkinson; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Phosphotransferase; prion‐like propagation; Proteins; Synuclein; Tissues and Organs; mitophagy; autophagy; neuroinflammation; mitochondria; prion-like propagation; neurodegeneration; aggregation; Parkinson; Prion-like propagation
• ISSN: 0953-816X; 1460-9568; 1460-9568
• DOI: 10.1111/ejn.14182

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.