Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

Sudipta Chakraborty, Pan Chen, Julia Bornhorst, Tanja Schwerdtle, Fabian Schumacher, Burkhard Kleuser, Aaron B. Bowman, Michael Aschner

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Overexposure to the essential metal manganese (Mn) can result in an irreversible condition known as manganism that shares similar pathophysiology with Parkinson's disease (PD), including dopaminergic (DAergic) cell loss that leads to motor and cognitive impairments. However, the mechanisms behind this neurotoxicity and its relationship with PD remain unclear. Many genes confer risk for autosomal recessive, early-onset PD, including the parkin/PARK2 gene that encodes for the E3 ubiquitin ligase Parkin. Using Caenorhabditis elegans (C. elegans) as an invertebrate model that conserves the DAergic system, we previously reported significantly increased Mn accumulation in pdr-1/parkin mutants compared to wildtype (WT) animals. For the current study, we hypothesize that this enhanced accumulation is due to alterations in Mn transport in the pdr-1 mutants. While no change in mRNA expression of the major Mn importer proteins (smf-1-3) was found in pdr-1 mutants, significant downregulation in mRNA levels of the putative Mn exporter ferroportin (fpn-1.1) was observed. Using a strain overexpressing fpn-1.1 in worms lacking pdr-1, we show evidence for attenuation of several endpoints of Mn-induced toxicity, including survival, metal accumulation, mitochondrial copy number and DAergic integrity, compared to pdr-1 mutants alone. These changes suggest a novel role of pdr-1 in modulating Mn export through altered transporter expression, and provides further support of metal dyshomeostasis as a component of Parkinsonism pathophysiology.

Original languageEnglish (US)
Pages (from-to)847-856
Number of pages10
JournalMetallomics
Volume7
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Caenorhabditis elegans
Manganese
Homeostasis
Metals
Parkinsonian Disorders
Parkinson Disease
Genes
Messenger RNA
Ubiquitin-Protein Ligases
Invertebrates
metal transporting protein 1
Toxicity
Animals
Down-Regulation
Proteins

ASJC Scopus subject areas

  • Biomaterials
  • Metals and Alloys
  • Chemistry (miscellaneous)
  • Biochemistry
  • Biophysics

Cite this

Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans. / Chakraborty, Sudipta; Chen, Pan; Bornhorst, Julia; Schwerdtle, Tanja; Schumacher, Fabian; Kleuser, Burkhard; Bowman, Aaron B.; Aschner, Michael.

In: Metallomics, Vol. 7, No. 5, 01.05.2015, p. 847-856.

Research output: Contribution to journalArticle

Chakraborty, S, Chen, P, Bornhorst, J, Schwerdtle, T, Schumacher, F, Kleuser, B, Bowman, AB & Aschner, M 2015, 'Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans', Metallomics, vol. 7, no. 5, pp. 847-856. https://doi.org/10.1039/c5mt00052a
Chakraborty S, Chen P, Bornhorst J, Schwerdtle T, Schumacher F, Kleuser B et al. Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans. Metallomics. 2015 May 1;7(5):847-856. https://doi.org/10.1039/c5mt00052a
Chakraborty, Sudipta ; Chen, Pan ; Bornhorst, Julia ; Schwerdtle, Tanja ; Schumacher, Fabian ; Kleuser, Burkhard ; Bowman, Aaron B. ; Aschner, Michael. / Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans. In: Metallomics. 2015 ; Vol. 7, No. 5. pp. 847-856.
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