title: Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1.
abstract: Alaskan Husky encephalopathy (AHE(1) ) 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.
authors.affiliation: Department of Surgical and Radiological Sciences, University of California Davis, Toronto, Ontario, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Vernau
authors.affiliation: Molecular Biosciences, University of California Davis, Toronto, Ontario, Canada.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Napoli
authors.affiliation: Molecular Biosciences, University of California Davis, Toronto, Ontario, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.affiliation: Molecular Biosciences, University of California Davis, Toronto, Ontario, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ross-Inta
authors.affiliation: Department of Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jessie
authors.initials: J
authors.lastname: Cameron
authors.affiliation: Pathology, Microbiology and Immunology, University of California Davis, Sacramento, CA.
authors.forename: Danika
authors.initials: D
authors.lastname: Bannasch
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California San Francisco.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bollen
authors.affiliation: Department of Surgical and Radiological Sciences, University of California Davis, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Dickinson
authors.affiliation: Molecular Biosciences, University of California Davis, Toronto, Ontario, Canada.|Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento, CA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D004272:DNA, Mitochondrial / Q000235:genetics; D004285:Dogs; D026901:Membrane Transport Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000209:etiology; D013831:Thiamine / Q000378:metabolism; D013832:Thiamine Deficiency / Q000235:genetics / Q000473:pathology / Q000662:veterinary
chemical_list: D004272:DNA, Mitochondrial; D026901:Membrane Transport Proteins; C492291:SLC19A3 protein, human; D013831:Thiamine
keywords: brain; mitochondrial dysfunction; mtDNA deletions; oxidative stress; thiamine deficiency