Department of Biochemistry and Microbiology, Nelson Mandela University, P.O. Box 77000, Port Elizabeth, 6031, South Africa.
Department of Biochemistry and Microbiology, Nelson Mandela University, P.O. Box 77000, Port Elizabeth, 6031, South Africa..
Toxicol Appl Pharmacol. 2020 Sep 15;403:115140. doi: 10.1016/j.taap.2020.115140. Epub 2020 Jul 17.
With accumulating evidence that supports the role of β-N-methylamino-l-alanine (BMAA) in neurodegeneration, it is necessary to elucidate the mechanisms and modes of BMAA toxicity so as to facilitate the search for potential preventative/therapeutic strategies. Daily supplementation with l-serine was suggested as a possible therapy to treat BMAA-induced neurotoxicity, based on the hypothesized mechanism of BMAA misincorporation into proteins for l-serine. As an alternative to misincorporation, it was hypothesized that BMAA toxicity may, in part, be due to its high affinity for associating with hydroxyl group-containing amino acids, and that a dietary excess of the hydroxyl-containing l-serine might offer protection by binding to BMAA and reducing its toxicity. Additionally, l-serine can also reduce the uptake of BMAA into human cells by competitive uptake at ASCT2, and l-phenylalanine, by competitive uptake at LAT1, and l-alanine, by competitive uptake at SNAT2, can also reduce BMAA uptake into human cells. The aim of this study was therefore to determine the protective value of l-serine, l-phenylalanine and l-alanine in reducing the effects of neonatal exposure to BMAA in a Sprague Dawley rat model. Pre-treatment with l-phenylalanine reduced the observed behavioral abnormalities and neuropathologies by 60-70% in most cases. l-serine was also effective in reducing some of the behavioral abnormalities and neuropathologies, most markedly spinal cord neuronal loss. However, the protective effect of l-serine was obfuscated by neuropathies that were observed in l-serine-treated control male rats. l-alanine had no effect in protecting against BMAA-induced neurotoxicity, suggesting that competitive amino acid uptake plays a minor role in protecting against BMAA-induced neurotoxicity.
随着越来越多的证据支持β-N-甲基氨基-l-丙氨酸（BMAA）在神经退行性变中的作用，有必要阐明 BMAA 毒性的机制和模式，以便促进寻找潜在的预防/治疗策略。基于 BMAA 错误掺入蛋白质以产生 l-丝氨酸的假设机制，每日补充 l-丝氨酸被认为是治疗 BMAA 诱导的神经毒性的一种可能疗法。作为错误掺入的替代方案，假设 BMAA 毒性可能部分归因于其与含羟基氨基酸高亲和力结合，并且富含羟基的 l-丝氨酸的饮食过量可能通过与 BMAA 结合并降低其毒性来提供保护。此外，l-丝氨酸还可以通过在 ASCT2 处的竞争性摄取，以及 l-苯丙氨酸在 LAT1 处的竞争性摄取和 l-丙氨酸在 SNAT2 处的竞争性摄取，减少 BMAA 进入人细胞的摄取，从而降低 BMAA 进入人细胞的摄取。因此，本研究的目的是确定 l-丝氨酸、l-苯丙氨酸和 l-丙氨酸在降低新生期暴露于 BMAA 的 Sprague Dawley 大鼠模型中影响的保护价值。在大多数情况下，l-苯丙氨酸预处理可使观察到的行为异常和神经病理学减少 60-70%。l-丝氨酸在降低一些行为异常和神经病理学方面也很有效，最明显的是脊髓神经元丢失。然而，l-丝氨酸对雄性对照大鼠神经病变的保护作用被混淆了。l-丙氨酸对 BMAA 诱导的神经毒性没有保护作用，这表明竞争性氨基酸摄取在保护 BMAA 诱导的神经毒性方面作用较小。
