Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1

Karen Vernau, Eleonora Napoli, Sarah Wong, Catherine Ross-Inta, Jessie Cameron, Danika L Bannasch, Andrew Bollen, Peter J Dickinson, Cecilia R Giulivi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Alaskan Husky encephalopathy (AHE<sup>1</sup>) is a fatal brain disease associated with a mutation in SLC19A3.1 (c.624insTTGC, c.625C>A). This gene encodes for a thiamine transporter 2 with a predominately (CNS) central nervous system distribution. Considering that brain is particularly vulnerable to thiamine deficiency because of its reliance on thiamine pyrophosphate (TPP)-dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha-helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation (OXPHOS) capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by Wernicke's and Korsakoff's syndromes, several differences were noted likely arising from a tissue-specific vs. that from a whole-body thiamine deficiency.

Original languageEnglish (US)
Pages (from-to)441-453
Number of pages13
JournalBrain Pathology
Volume25
Issue number4
DOIs
StatePublished - Jul 1 2015

Fingerprint

Thiamine Deficiency
Pathology
Thiamine
Mutation
Thiamine Pyrophosphate
Brain
Oxidative Stress
Brain Diseases
Energy Metabolism
Korsakoff Syndrome
Phenotype
Aptitude
Oxidative Phosphorylation
Metabolic Networks and Pathways
Thalamus
Computer Simulation
Cerebral Cortex
Neurotransmitter Agents
Central Nervous System
Dogs

Keywords

  • brain
  • mitochondrial dysfunction
  • mtDNA deletions
  • oxidative stress
  • thiamine deficiency

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pathology and Forensic Medicine
  • Clinical Neurology

Cite this

Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1. / Vernau, Karen; Napoli, Eleonora; Wong, Sarah; Ross-Inta, Catherine; Cameron, Jessie; Bannasch, Danika L; Bollen, Andrew; Dickinson, Peter J; Giulivi, Cecilia R.

In: Brain Pathology, Vol. 25, No. 4, 01.07.2015, p. 441-453.

Research output: Contribution to journalArticle

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abstract = "Alaskan Husky encephalopathy (AHE1) is a fatal brain disease associated with a mutation in SLC19A3.1 (c.624insTTGC, c.625C>A). This gene encodes for a thiamine transporter 2 with a predominately (CNS) central nervous system distribution. Considering that brain is particularly vulnerable to thiamine deficiency because of its reliance on thiamine pyrophosphate (TPP)-dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha-helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation (OXPHOS) capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by Wernicke's and Korsakoff's syndromes, several differences were noted likely arising from a tissue-specific vs. that from a whole-body thiamine deficiency.",
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