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PMID: 20881132 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ß.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 30 ·No. 39 ·2010-09-29 ·Pages 13138-49

Lin CH, Tsai PI, Wu RM, Chien CT

Abstract

Intraneuronal tau aggregations are distinctive pathological features of Parkinson's disease (PD) with autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2). The most prevalent LRRK2 mutation, G2019S (glycine to serine substitution at amino acid 2019), causes neurite shrinkage through unclear pathogenetic mechanisms. We found that expression of G2019S mutant in Drosophila dendritic arborization neurons induces mislocalization of the axonal protein tau in dendrites and causes dendrite degeneration. G2019S-induced dendrite degeneration is suppressed by reducing the level of tau protein and aggravated by tau coexpression. Additional genetic analyses suggest that G2019S and tau function synergistically to cause microtubule fragmentation, inclusion formation, and dendrite degeneration. Mechanistically, hyperactivated G2019S promotes tau phosphorylation at the T212 site by the Drosophila glycogen synthase kinase 3β homolog Shaggy (Sgg). G2019S increases the recruitment of autoactivated Sgg, thus inducing hyperphosphorylation and mislocalization of tau with resultant dendrite degeneration.

MeSH Terms
Amino Acid Substitution/genetics Animals Animals, Genetically Modified Dendrites/enzymology,pathology Drosophila Proteins/metabolism,physiology Drosophila melanogaster Enzyme Activation/genetics Glycogen Synthase Kinase 3/metabolism,physiology Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Mutation/genetics Nerve Degeneration/enzymology,genetics,pathology Phosphorylation/genetics Protein Serine-Threonine Kinases/genetics,physiology tau Proteins/metabolism
Chemicals
Drosophila Proteins tau Proteins LRRK2 protein, human Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Protein Serine-Threonine Kinases Sgg protein, Drosophila Glycogen Synthase Kinase 3
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Lin Chin-Hsien
Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
Tsai Pei-I
Wu Ruey-Meei
Chien Cheng-Ting
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1737-10.2010
Published
2010-09-29
Pages
13138-49
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6633523
Subset
IM
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1737-10.2010 PMC Full Text View journal details
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