Logo image
Back
Kinase activity is required for the toxic effects of mutant LRRK2/dardarin
Journal article   Peer reviewed

Kinase activity is required for the toxic effects of mutant LRRK2/dardarin

E Greggio, S Jain, A Kingsbury, R Bandopadhyay, P Lewis, A Kaganovich, M P van der Brug, A Beilina, J Blackinton, K J Thomas, …
Neurobiology of Disease, Vol.23(2), pp.329-341
2006
DOI: https://doi.org/10.1016/j.nbd.2006.04.001
url
https://doi.org/10.1016/j.nbd.2006.04.001View
Published Version

Abstract

LRRK2 kinase Parkinson's disease α-synuclein substantia nigra
Mutations in the LRRK2 gene, coding for dardarin, cause dominantly inherited Parkinson's disease (PD). Dardarin is a large protein, and mutations are found throughout the gene including the kinase domain. However, it is not clear if kinase activity is important for the damaging effects of pathogenic mutations. In this study, we noted two cellular phenotypes associated with mutant dardarin. First, pathogenic mutations increase the tendency of dardarin to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein. Manipulating activity by replacing the kinase domain with a 'kinase-dead' version blocks inclusion body formation and strongly delays cell death. This predicts that kinase inhibitors will be useful therapeutic agents in patients with LRRK2 mutations and, perhaps, in sporadic PD. We also show that dardarin protein is expressed within human midbrain neurons and that C-terminal epitopes are also found in some Lewy bodies.

Details

Metrics

269 Record Views
623 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types
Domestic collaboration
International collaboration
Web Of Science research areas
Neurosciences

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

Source: InCites

Logo image