Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, CA, USA.
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
Mol Metab. 2023 Jun;72:101716. doi: 10.1016/j.molmet.2023.101716. Epub 2023 Mar 28.
The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both.
We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants.
MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and glycine restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins.
These results highlight metabolic distinctions between MacTel and HSAN1, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches for these two neurodegenerative diseases.
非必需氨基酸丝氨酸、甘氨酸和丙氨酸，以及多种神经鞘脂类物质，都与遗传性神经视网膜疾病有关，并且通过丝氨酸棕榈酰转移酶（SPT）代谢相关，SPT 是膜脂质生物发生的关键酶。为了深入了解将这些途径与神经视网膜疾病联系起来的病理生理机制，我们比较了两种代谢相互交织的疾病患者：II 型黄斑毛细血管扩张症（MacTel）、遗传性感觉自主神经病 1 型（HSAN1）或两者兼有。
我们对 MacTel（205 例）、HSAN1（25 例）和对照组（151 例）参与者的血清进行了靶向代谢组学分析，检测氨基酸和广泛的神经鞘脂类物质。
MacTel 患者表现出广泛的氨基酸变化，包括丝氨酸、甘氨酸、丙氨酸、谷氨酸和支链氨基酸的变化，这些变化类似于糖尿病。MacTel 患者的 1-脱氧神经鞘脂类物质升高，但循环中复杂神经鞘脂类物质的水平降低。视网膜病变的小鼠模型表明，饮食中丝氨酸和甘氨酸的限制可以导致复杂神经鞘脂类物质的消耗。与对照组相比，HSAN1 患者表现出丝氨酸升高、丙氨酸降低，以及经典神经酰胺和神经鞘磷脂减少。同时患有 HSAN1 和 MacTel 的患者表现出循环中神经鞘磷脂降低最明显。
这些结果突出了 MacTel 和 HSAN1 之间的代谢差异，强调了膜脂质在 MacTel 进展中的重要性，并为这两种神经退行性疾病提出了不同的治疗方法。
