Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation inSLC19A3.1
Autor: | Andrew W. Bollen, Jessie M. Cameron, Danika L. Bannasch, Sarah Wong, Catherine Ross-Inta, Eleonora Napoli, Karen M. Vernau, Peter J Dickinson, Cecilia R Giulivi |
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Rok vydání: | 2014 |
Předmět: |
medicine.medical_specialty
biology Thiamine transport General Neuroscience Encephalopathy food and beverages Mitochondrion medicine.disease medicine.disease_cause Pathology and Forensic Medicine chemistry.chemical_compound Endocrinology chemistry Biochemistry Internal medicine SLC19A3 medicine biology.protein Thiamine transporter Thiamine Neurology (clinical) human activities Thiamine pyrophosphate Oxidative stress |
Zdroj: | Brain Pathology. 25:441-453 |
ISSN: | 1015-6305 |
Popis: | 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. |
Databáze: | OpenAIRE |
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