Format

Send to

Choose Destination
See comment in PubMed Commons below
J Neurosci. 2014 Jan 8;34(2):418-33. doi: 10.1523/JNEUROSCI.2712-13.2014.

Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies.

Author information

  • 1Gladstone Institute of Neurological Disease, the Taube-Koret Center for Neurodegenerative Disease Research, and the Hellman Family Foundation Program in Alzheimer's Disease Research, San Francisco, California 94158, Departments of Neurology, Physiology, and Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, California 94158, and Laboratory of Neurogenetics, National Institutes of Health, Bethesda, Maryland 20892.

Abstract

By combining experimental neuron models and mathematical tools, we developed a "systems" approach to deconvolve cellular mechanisms of neurodegeneration underlying the most common known cause of Parkinson's disease (PD), mutations in leucine-rich repeat kinase 2 (LRRK2). Neurons ectopically expressing mutant LRRK2 formed inclusion bodies (IBs), retracted neurites, accumulated synuclein, and died prematurely, recapitulating key features of PD. Degeneration was predicted from the levels of diffuse mutant LRRK2 that each neuron contained, but IB formation was neither necessary nor sufficient for death. Genetic or pharmacological blockade of its kinase activity destabilized LRRK2 and lowered its levels enough to account for the moderate reduction in LRRK2 toxicity that ensued. By contrast, targeting synuclein, including neurons made from PD patient-derived induced pluripotent cells, dramatically reduced LRRK2-dependent neurodegeneration and LRRK2 levels. These findings suggest that LRRK2 levels are more important than kinase activity per se in predicting toxicity and implicate synuclein as a major mediator of LRRK2-induced neurodegeneration.

KEYWORDS:

LRRK2; Parkinson's disease; mechanisms; single cell; synuclein

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk