RRC ID 46689
Author Wiese M, Antebi A, Zheng H.
Title Intracellular trafficking and synaptic function of APL-1 in Caenorhabditis elegans.
Journal PLoS One
Abstract BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by the deposition of β-amyloid plaques in the brain. Plaques are composed of the amyloid-β peptide derived from cleavage of the amyloid precursor protein (APP). Mutations in APP lead to the development of Familial Alzheimer's Disease (FAD), however, the normal function of this protein has proven elusive. The organism Caenorhabditis elegans is an attractive model as the amyloid precursor-like protein (APL-1) is the single ortholog of APP, and loss of apl-1 leads to a severe molting defect and early larval lethality.
METHODOLOGY/PRINCIPAL FINDINGS:We report here that lethality and molting can be rescued by full length APL-1, C-terminal mutations as well as a C-terminal truncation, suggesting that the extracellular region of the protein is essential for viability. RNAi knock-down of apl-1 followed by drug testing on the acetylcholinesterase inhibitor aldicarb showed that loss of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. The aldicarb hypersensitivity can be rescued by full length APL-1 in a dose dependent fashion. At the cellular level, kinesins UNC-104/KIF-1A and UNC-116/kinesin-1 are positive regulators of APL-1 expression in the neurons. Knock-down of the small GTPase rab-5 also leads to a dramatic decrease in the amount of apl-1 expression in neurons, suggesting that trafficking from the plasma membrane to the early endosome is important for apl-1 function. Loss of function of a different small GTPase, UNC-108, on the contrary, leads to the retention of APL-1 in the cell body.
CONCLUSIONS/SIGNIFICANCE:Our results reveal novel insights into the intracellular trafficking of APL-1 and we report a functional role for APL-1 in synaptic transmission.
Volume 5(9)
Published 2010-9-20
DOI 10.1371/journal.pone.0012790
PII e12790
PMID 20862215
PMC PMC2942829
MeSH Alzheimer Disease / genetics Alzheimer Disease / metabolism Amino Acid Motifs Animals Caenorhabditis elegans / chemistry Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Membrane / chemistry Cell Membrane / genetics Cell Membrane / metabolism Disease Models, Animal Endosomes / chemistry Endosomes / genetics Endosomes / metabolism Humans Membrane Proteins / chemistry Membrane Proteins / genetics Membrane Proteins / metabolism* Molting Monomeric GTP-Binding Proteins / genetics Monomeric GTP-Binding Proteins / metabolism Neurons / metabolism Protein Transport Synapses / chemistry Synapses / genetics Synapses / metabolism* Synaptic Transmission*
IF 2.74
Times Cited 31
Resource
C.elegans tm385