Homocysteine Homeostasis and Betaine-Homocysteine S-Methyltransferase Expression in the Brain of Hibernating Bats

Elevated homocysteine is an important risk factor that increases cerebrovascular and neurodegenerative disease morbidity. In mammals, B vitamin supplementation can reduce homocysteine levels. Whether, and how, hibernating mammals, that essentially stop ingesting B vitamins, maintain homocysteine metabolism and avoid cerebrovascular impacts and neurodegeneration remain unclear. Here, we compare homocysteine levels in the brains of torpid bats, active bats and rats to identify the molecules involved in homocysteine homeostasis. We found that homocysteine does not elevate in torpid brains, despite declining vitamin B levels. At low levels of vitamin B6 and B12, we found no change in total expression level of the two main enzymes involved in homocysteine metabolism (methionine synthase and cystathionine β-synthase), but a 1.85-fold increase in the expression of the coenzyme-independent betaine-homocysteine S-methyltransferase (BHMT). BHMT expression was observed in the amygdala of basal ganglia and the cerebral cortex where BHMT levels were clearly elevated during torpor. This is the first report of BHMT protein expression in the brain and suggests that BHMT modulates homocysteine in the brains of hibernating bats. BHMT may have a neuroprotective role in the brains of hibernating mammals and further research on this system could expand our biomedical understanding of certain cerebrovascular and neurodegenerative disease processes.

同型半胱氨酸（homocysteine）水平升高是增加脑血管疾病与神经退行性疾病发病率的重要危险因素。在哺乳动物体内，补充B族维生素可降低同型半胱氨酸水平。对于几乎完全停止摄入B族维生素的冬眠哺乳动物而言，它们如何维持同型半胱氨酸代谢、并避免脑血管损伤与神经退行性病变，目前仍不明确。本研究通过比较蛰伏蝙蝠、活跃蝙蝠与大鼠的脑组织同型半胱氨酸水平，鉴定参与同型半胱氨酸稳态（homocysteine homeostasis）调控的分子。研究发现，尽管脑组织内B族维生素水平下降，但蛰伏状态下的蝙蝠脑组织中同型半胱氨酸水平并未升高。在维生素B6与B12水平较低的情况下，我们并未观察到参与同型半胱氨酸代谢的两种核心酶——甲硫氨酸合酶（methionine synthase）与胱硫醚β合酶（cystathionine β-synthase）——的总表达量发生变化，但非辅酶依赖型甜菜碱-同型半胱氨酸S-甲基转移酶（betaine-homocysteine S-methyltransferase，BHMT）的表达量上调了1.85倍。研究发现，BHMT在基底神经节（basal ganglia）的杏仁核（amygdala）与大脑皮层（cerebral cortex）中均有表达，且在蛰伏状态下该酶的表达水平显著升高。本研究首次报道了BHMT蛋白在脑组织中的表达，并提示BHMT可调控冬眠蝙蝠脑组织内的同型半胱氨酸水平。BHMT可能在冬眠哺乳动物的脑组织中发挥神经保护作用，针对该调控系统的后续研究将有助于深化我们对部分脑血管疾病与神经退行性疾病病理过程的生物医学认知。