High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3-deficient mice.

Kaoru Suzuki,Kenichiro Yamada,Yayoi Fukuhara,Katsumi Shibata,Nobuaki Wakamatsu,Ai Tsuji,G William Wong

doi:10.1371/journal.pone.0180279

Kaoru Suzuki, Kenichiro Yamada + Show 5 more

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https://doi.org/10.1371/journal.pone.0180279

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Abstract

SLC19A3 deficiency, also called thiamine metabolism dysfunction syndrome-2 (THMD2; OMIM 607483), is an autosomal recessive neurodegenerative disorder caused by mutations in SLC19A3, the gene encoding thiamine transporter 2. To investigate the molecular mechanisms of neurodegeneration in SLC19A3 deficiency and whether administration of high-dose thiamine prevents neurodegeneration, we generated homozygous Slc19a3 E314Q knock-in (KI) mice harboring the mutation corresponding to the human SLC19A3 E320Q, which is associated with the severe form of THMD2. Homozygous KI mice and previously reported homozygous Slc19a3 knock-out (KO) mice fed a thiamine-restricted diet (thiamine: 0.60 mg/100 g food) died within 30 and 12 days, respectively, with dramatically decreased thiamine concentration in the blood and brain, acute neurodegeneration, and astrogliosis in the submedial nucleus of the thalamus and ventral anterior-lateral complex of the thalamus. These findings may bear some features of thiamine-deficient mice generated by pyrithiamine injection and a thiamine-deficient diet, suggesting that the primary cause of THMD2 could be thiamine pyrophosphate (TPP) deficiency. Next, we analyzed the therapeutic effects of high-dose thiamine treatment. When the diet was reverted to a conventional diet (thiamine: 1.71 mg/100 g food) after thiamine restriction, all homozygous KO mice died. In contrast, when the diet was changed to a high-thiamine diet (thiamine: 8.50 mg/100 g food) after thiamine restriction, more than half of homozygous KO mice survived, without progression of brain lesions. Unexpectedly, when the high-thiamine diet of recovered mice was reverted to a conventional diet, some homozygous KO mice died. These results showed that acute neurodegeneration caused by thiamine deficiency is preventable in most parts, and prompt high-dose thiamine administration is critical for the treatment of THMD2. However, reduction of thiamine should be performed carefully to prevent recurrence after recovery of the disease.

Highlights

IntroductionThiamine ( known as vitamin B1) is an essential water-soluble vitamin. The body cannot produce thiamine and can only store approximately 30 mg of it in skeletal muscles, brain, heart, liver, and kidneys [1]
Effect of thiamine restriction on thiamine concentration in the blood and brain Thiamine levels in the blood of homozygous KO and KI mice fed a conventional diet were decreased to 0.058 ± 0.051 and 0.126 ± 0.092 nmol/mL, respectively, at 7 weeks compared to WT mice (0.796 ± 0.259 nmol/mL) (Fig 2A)
When WT and homozygous KO and KI mice were fed a thiamine-restricted diet, blood thiamine concentration at 5 and 14 days was markedly decreased to 0.010 ± 0.009 and 0.010 ± 0.006 nmol/mL, respectively, compared to WT mice (0.609 ± 0.288 nmol/mL) (Fig 2A)

Summary

Introduction

Thiamine ( known as vitamin B1) is an essential water-soluble vitamin. The body cannot produce thiamine and can only store approximately 30 mg of it in skeletal muscles, brain, heart, liver, and kidneys [1]. Thiamine is transported into cells mainly by two thiamine transporters (SLC19A2 and SLC19A3) [3, 4]. SLC19A2 is expressed in skeletal muscles and systemic tissues, whereas SLC19A3 is expressed predominantly in the upper intestine and the duodenum [5, 6]. Thiamine is absorbed mainly at the duodenum by SLC19A3 and transported into tissues and cells by SLC19A2 and SLC19A3. TPP is incorporated into four known mammalian enzymes in cellular metabolism: transketolase, involved in the pentose phosphate pathway; pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, associated with the tricarboxylic acid (TCA) cycle; and branched chain α-keto acid dehydrogenase complex, involved in the catabolism of the three branched-chain amino acids (leucine, isoleucine, and valine) [9]. Thiamine is critically important as a cofactor of enzymes associated with ATP generation at mitochondria via the TCA cycle

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