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

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 predominantely central nervous system (CNS) distribution. Considering that brain is particularly vulnerable to thiamine deficiency due to its reliance on 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 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.

A novel encephalopathy in a thiamine-deficient dog resembling human Wernicke’s disease with atypical MRI pattern

“…Neurological signs are most commonly reported and include depression, dilated unresponsive pupils, positional vertical nystagmus, mild ataxia, seizures, hyperesthesia, abnormal behaviour, upper motor neuron tetraparesis, and opisthotonus (Garosi et al, 2003). A fatal brain disease associated with a genetic mutation for the gene encoding for a thiamine transporter predominantly within the central nervous system has been described in an Alaskan Husky (Vernau et al, 2015). In our patient the overall clinical presentation differed from that previously described for TD in dogs (Platt and Garosi, 2012) and it was characterized by multifocal, central and peripheral nervous and cardiovascular system alterations.…”

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

“…94 The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation capacity, and increases in oxidative stress. 95 Moreover, KO and KI (for E320Q equivalent mice position) mice models have been generated. 88,96 These mice models showed a reduction in intestinal thiamine uptake associated with a depletion of thiamine levels in blood when fed with a thiamine-restricted diet.…”

Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy

“…TD adversely affects many organ systems including the cardiovascular [18], muscular [19], gastrointestinal [20], and central and peripheral nervous systems [21]. The central nervous system (CNS) is particularly sensitive to TD, because of its dependence on TPP-mediated metabolic pathways involved in energy metabolism and neurotransmitter synthesis [22]. Insufficient levels of thiamine causes neurological and metabolic disorders which may be corrected by thiamine administration.…”