Increased actin polymerization and stabilization interferes with neuronal function and survival in the AMPKγ mutant loechrig

Mandy Cook, Bonnie J. Bolkan, Doris Kretzschmar

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

loechrig (loe) mutant flies are characterized by progressive neuronal degeneration, behavioral deficits, and early death. The mutation is due to a P-element insertion in the gene for the γ-subunit of the trimeric AMP-activated protein kinase (AMPK) complex, whereby the insertion affects only one of several alternative transcripts encoding a unique neuronal isoform. AMPK is a cellular energy sensor that regulates a plethora of signaling pathways, including cholesterol and isoprenoid synthesis via its downstream target hydroxy-methylglutaryl (HMG)-CoA reductase. We recently showed that loe interferes with isoprenoid synthesis and increases the prenylation and thereby activation of RhoA. During development, RhoA plays an important role in neuronal outgrowth by activating a signaling cascade that regulates actin dynamics. Here we show that the effect of loe/AMPKγ on RhoA prenylation leads to a hyperactivation of this signaling pathway, causing increased phosphorylation of the actin depolymerizating factor cofilin and accumulation of filamentous actin. Furthermore, our results show that the resulting cytoskeletal changes in loe interfere with neuronal growth and disrupt axonal integrity. Surprisingly, these phenotypes were enhanced by expressing the Slingshot (SSH) phosphatase, which during development promotes actin depolymerization by dephosphorylating cofilin. However, our studies suggest that in the adult SSH promotes actin polymerization, supporting in vitro studies using human SSH1 that suggested that SSH can also stabilize and bundle filamentous actin. Together with the observed increase in SSH levels in the loe mutant, our experiments suggest that in mature neurons SSH may function as a stabilization factor for filamentous actin instead of promoting actin depolymerization

Original languageEnglish (US)
Article numbere89847
JournalPLoS One
Volume9
Issue number2
DOIs
StatePublished - Feb 25 2014

Fingerprint

AMP-activated protein kinase
AMP-Activated Protein Kinases
Polymerization
polymerization
actin
Actins
Stabilization
mutants
Survival
Actin Depolymerizing Factors
Prenylation
Depolymerization
depolymerization
isoprenoids
Terpenes
Phosphorylation
synthesis
Insertional Mutagenesis
Coenzyme A
Phosphoric Monoester Hydrolases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Increased actin polymerization and stabilization interferes with neuronal function and survival in the AMPKγ mutant loechrig. / Cook, Mandy; Bolkan, Bonnie J.; Kretzschmar, Doris.

In: PLoS One, Vol. 9, No. 2, e89847, 25.02.2014.

Research output: Contribution to journalArticle

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