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CLN3 deficient cells display defects in the ARF1-Cdc42 pathway and actin-dependent events
Journal article   Open access   Peer reviewed

CLN3 deficient cells display defects in the ARF1-Cdc42 pathway and actin-dependent events

Mark L Schultz, Luis Tecedor, Colleen S Stein, Mark A Stamnes and Beverly L Davidson
PloS one, Vol.9(5), pp.e96647-e96647
2014
DOI: 10.1371/journal.pone.0096647
PMCID: PMC4008583
PMID: 24792215
url
https://doi.org/10.1371/journal.pone.0096647View
Published (Version of record) Open Access

Abstract

Juvenile Batten disease (juvenile neuronal ceroid lipofuscinosis, JNCL) is a devastating neurodegenerative disease caused by mutations in CLN3, a protein of undefined function. Cell lines derived from patients or mice with CLN3 deficiency have impairments in actin-regulated processes such as endocytosis, autophagy, vesicular trafficking, and cell migration. Here we demonstrate the small GTPase Cdc42 is misregulated in the absence of CLN3, and thus may be a common link to multiple cellular defects. We discover that active Cdc42 (Cdc42-GTP) is elevated in endothelial cells from CLN3 deficient mouse brain, and correlates with enhanced PAK-1 phosphorylation, LIMK membrane recruitment, and altered actin-driven events. We also demonstrate dramatically reduced plasma membrane recruitment of the Cdc42 GTPase activating protein, ARHGAP21. In line with this, GTP-loaded ARF1, an effector of ARHGAP21 recruitment, is depressed. Together these data implicate misregulated ARF1-Cdc42 signaling as a central defect in JNCL cells, which in-turn impairs various cell functions. Furthermore our findings support concerted action of ARF1, ARHGAP21, and Cdc42 to regulate fluid phase endocytosis in mammalian cells. The ARF1-Cdc42 pathway presents a promising new avenue for JNCL therapeutic development.
 Brain - cytology Molecular Chaperones - metabolism Membrane Glycoproteins - metabolism Signal Transduction Endothelial Cells - metabolism Humans Mice, Inbred C57BL Actins - metabolism Cells, Cultured Molecular Chaperones - genetics Neuronal Ceroid-Lipofuscinoses - metabolism cdc42 GTP-Binding Protein - metabolism Neuronal Ceroid-Lipofuscinoses - pathology Membrane Glycoproteins - genetics Brain - metabolism Endocytosis Animals Neuronal Ceroid-Lipofuscinoses - genetics Gene Deletion Brain - pathology ADP-Ribosylation Factor 1 - metabolism Mice Endothelial Cells - pathology Cell Movement

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