Effects of Paraquat, Dextran Sulfate Sodium, and Irradiation on Behavioral and Cognitive Performance and the Gut Microbiome in A53T and A53T-L444P Mice

Ariel Chaklai, Abigail O’Neil, Shrey Goel, Nick Margolies, Destine Krenik, Ruby Perez, Kat Kessler, Elizabeth Staltontall, Hong Ki Yoon, Montzerrat Pantoja, Keaton Stagaman, Kristin Kasschau, Vivek Unni, Robert Duvoisin, Thomas Sharpton, Jacob Raber

Research output: Contribution to journalArticlepeer-review

Abstract

Heterozygous carriers of the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased risk of developing Parkinson’s disease (PD). The GBA mutations result in elevated alpha synuclein (aSyn) levels. Heterozygous mice carrying one allele with the L444P mutation knocked-into the mouse gene show increased aSyn levels and are more sensitive to motor deficits following exposure to the neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP than wild-type mice. Paraquat (PQ), a herbicide, increases PD risk in most studies. Its effects on the brain involve alterations in the gut microbiome. Exposure to dextran sulfate sodium (DSS), a mouse model of colitis, can be used to determine whether gut microbiome alterations are sufficient to induce PD-relevant phenotypes. We rederived the A53T-L444P and A53T mouse lines to assess whether PQ, PQ in combination with radiation exposure (IR), and DSS have differential effects in A53T and A53T-L444P mice and whether these effects are associated with alterations in the gut microbiome. PQ and PQ + IR have differential effects in A53T and A53T-L444P mice. In contrast, effects of DSS are only seen in A53T-L444P mice. Exposure and genotype modulate the relationship between the gut microbiome and behavioral performance. The gut microbiome may be an important mediator of how environmental exposures or genetic mutations yield behavioral and cognitive impacts.

Original languageEnglish (US)
Article number282
JournalGenes
Volume15
Issue number3
DOIs
StatePublished - Mar 2024

Keywords

  • Gaucher mutation
  • alpha synuclein mutation
  • behavioral testing
  • cognitive testing
  • dextran sulfate sodium
  • gut microbiome
  • irradiation
  • paraquat

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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