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Planta

, Volume 242, Issue 4, pp 921–933 | Cite as

Misexpression of the Niemann-Pick disease type C1 (NPC1)-like protein in Arabidopsis causes sphingolipid accumulation and reproductive defects

  • Maximilian J. Feldman
  • Brenton C. Poirier
  • B. Markus LangeEmail author
Original Article

Abstract

Main conclusion

Misexpression of the AtNPC1 - 1 and AtNPC1 - 2 genes leads to altered sphingolipid metabolism, growth impairment, and male reproductive defects in a hemizygous Arabidopsis thaliana (L.) double-mutant population. Abolishing the expression of both gene copies has lethal effects.

Abstract

Niemann-Pick disease type C1 is a lysosomal storage disorder caused by mutations in the NPC1 gene. At the cellular level, the disorder is characterized by the accumulation of storage lipids and lipid trafficking defects. The Arabidopsis thaliana genome contains two genes (At1g42470 and At4g38350) with weak homology to mammalian NPC1. The corresponding proteins have 11 predicted membrane-spanning regions and contain a putative sterol-sensing domain. The At1g42470 protein is localized to the plasma membrane, while At4g38350 protein has a dual localization in the plasma and tonoplast membranes. A phenotypic analysis of T-DNA insertion mutants indicated that At1g42470 and At4g38350 (designated AtNPC1-1 and AtNPC1-2, respectively) have partially redundant functions and are essential for plant reproductive viability and development. Homozygous plants impaired in the expression of both genes were not recoverable. Plants of a hemizygous AtNPC1-1/atnpc1-1/atnpc1-2/atnpc1-2 population were severely dwarfed and exhibited male gametophytic defects. These gene disruptions did not have an effect on sterol concentrations; however, hemizygous AtNPC1-1/atnpc1-1/atnpc1-2/atnpc1-2 mutants had increased fatty acid amounts. Among these, fatty acid α-hydroxytetracosanoic acid (h24:0) occurs in plant sphingolipids. Follow-up analyses confirmed the accumulation of significantly increased levels of sphingolipids (assayed as hydrolyzed sphingoid base component) in the hemizygous double-mutant population. Certain effects of NPC1 misexpression may be common across divergent lineages of eukaryotes (sphingolipid accumulation), while other defects (sterol accumulation) may occur only in certain groups of eukaryotic organisms.

Keywords

Male gametophyte Niemann–Pick disease type C1 Sphingolipid Sterol-sensing domain 

Abbreviations

GC–MS

Gas chromatography–mass spectrometry

GO

Gene ontology

HMGR

3-hydroxy-3-methylglutaryl-coenzyme A reductase

LE/Lys

Late endosomal/lysosomal compartment

NPC1

Niemann-Pick disease type C1

SBH

Sphingoid base hydroxylase

SCAP

SREBP cleavage activating protein

SPT

Serine palmitoyltransferase

SREBP

Sterol regulatory element binding protein

SSD

Sterol-sensing domain

Notes

Acknowledgments

This work was supported by grants from the National Science Foundation (NSF-MCB-0920758) and the Agricultural Research Center at Washington State University (both to B. M. L.). We are grateful for the advice of Dr. Laura Wayne for the analysis of genotypic ratios. We would also like to thank Ms. Iris Lange for technical assistance and Ms. Julia Gothard for help with growing plants. Standards and reagents for the sphingoid base and galactolipid analyses were purchased with funds from a Global Plant Sciences Initiative (GPSI) fellowship.

Supplementary material

425_2015_2322_MOESM1_ESM.jpg (220 kb)
Supplementary material 1 (JPEG 220 kb). Supplementary Fig. S1 Representative dwarf phenotype of an Arabidopsis line obtained from crosses of plants containing the mutant allele atnpc1-2-2
425_2015_2322_MOESM2_ESM.jpg (76 kb)
Supplementary material 2 (JPEG 75 kb). Supplementary Fig. S2 Determination of chlorophyll concentrations in rosette leaves of wild-type and mutant plants (n = 5). Filling: wild-type, white; AtNPC1-1-1/atnpc1-1-1/atnpc1-2-1/atnpc1-2-1 mutant, gray
425_2015_2322_MOESM3_ESM.docx (12 kb)
Supplementary material 3 (DOCX 12 kb). Supplementary Fig. S3 Alignment of the N-terminal sterol binding domains (putative) of NPC1 from Arabidopsis thaliana (At1g42470 and At4g38350) and Homo sapiens (O15118). Residues forming the sterol binding pocket in the human ortholog are depicted with a yellow background, while the residues required for sterol transfer from NPC2 are highlighted by red background
425_2015_2322_MOESM4_ESM.jpg (604 kb)
Supplementary material 4 (JPEG 604 kb). Supplementary Fig. S4 Tissue-level expression patterns of Arabidopsis thaliana a NPC1-1 (At1g42470) and b NPC1-2 (At4g38350)
425_2015_2322_MOESM5_ESM.jpg (541 kb)
Supplementary material 5 (JPEG 541 kb). Supplementary Fig. S5 Gene ontology terms enriched in the annotation of a list of Arabidopsis thaliana genes with expression patterns similar to those of NPC1-1 (At1g42470)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Maximilian J. Feldman
    • 1
  • Brenton C. Poirier
    • 2
  • B. Markus Lange
    • 2
    Email author
  1. 1.Donald Danforth Plant Science CenterSt. LouisUSA
  2. 2.Institute of Biological Chemistry and M.J. Murdock Metabolomics LaboratoryWashington State UniversityPullmanUSA

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