Activation of Lrrk2 and α-Synuclein in substantia nigra, striatum, and cerebellum after chronic exposure to arsenite

Toxicol Appl Pharmacol. 2020 Dec 1;408:115278. doi: 10.1016/j.taap.2020.115278. Epub 2020 Oct 11.

Abstract

Arsenic is a neurotoxin and environmental exposure to it correlates with an incidence of neurodegenerative diseases. Considering that arsenic has the potential to inhibit autophagic flux, it was hypothesized that arsenite (NaAsO2) may interplay with LRRK2 and α-Synuclein, affecting their phosphorylation in brain regions prone to neurodegeneration. After 15 weeks of chronic exposure to arsenite, a reduction in grip strength of C57BL/6 male mice was observed. Thirty minutes exposure to arsenite increased phosphorylation of Lrrk2 and α-Synuclein in organotypic brain slice cultures from the cerebellum and striatum, respectively. Chronic exposure of mice to a wide-range of concentrations of arsenite led to a significant induction of Lrrk2 phosphorylation in substantia nigra and cerebellum and α-Synuclein phosphorylation in substantia nigra and striatum. Strong correlations between phosphorylated forms of Lrrk2 and α-Synuclein in substantia nigra, Lrrk2 levels between substantia nigra and striatum, and between Lrrk2 in striatum and α-Synuclein in substantia nigra observed in control animals were completely disrupted by arsenic exposure at 50, 500, and 5000 ppb. A transcriptome analysis identified specific genes and canonical pathways that distinguish striatum, substantia nigra, and cerebellum from each other in control animals and compare individual brain regions to arsenite exposed animals. Chronic arsenite exposure altered transcripts of glutathione redox reactions and serotonin receptor signaling in striatum, axonal guidance signaling, NF-κB and androgen signaling in substantia nigra and mitochondrial dysfunction, oxidative phosphorylation, apoptosis and sirtuin signaling in the cerebellum. These data suggest that arsenite affects processes associated with neurodegenerative diseases in brain region specific manner.

Keywords: Arsenite; Cerebellum; Lrrk2; Striatum; Substantia nigra; α-Synuclein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arsenic Poisoning / genetics
  • Arsenic Poisoning / metabolism
  • Arsenic Poisoning / physiopathology
  • Arsenites / toxicity*
  • Cerebellum / drug effects*
  • Cerebellum / metabolism
  • Corpus Striatum / drug effects*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Muscle Strength / drug effects
  • Phosphorylation / drug effects
  • Substantia Nigra / drug effects*
  • Substantia Nigra / metabolism
  • Transcriptome / drug effects
  • alpha-Synuclein / metabolism*

Substances

  • Arsenites
  • alpha-Synuclein
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • arsenite