Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease.
Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease.
复制标题
遗传性神经视网膜疾病患者的不同氨基酸和鞘脂代谢。
DOI：
10.1016/j.molmet.2023.101716
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发表时间：
2023
影响因子：
8.1
通讯作者：
中科院分区：
文献类型：
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作者：
Green,CourtneyR;Bonelli,Roberto;Ansell,BrendanRE;Tzaridis,Simone;Handzlik,MichalK;McGregor,GraceH;Hart,Barbara;Trombley,Jennifer;Reilly,MaryM;Bernstein,PaulS;Egan,Catherine;Fruttiger,Marcus;Wallace,Martina;Bahlo,Melanie;
目的非必需氨基酸丝氨酸、甘氨酸和丙氨酸以及多种鞘脂与遗传性神经视网膜疾病有关，并通过丝氨酸棕榈酰转移酶（SPT）进行代谢联系，SPT是膜脂质生物合成的关键酶。为了深入了解将这些通路与神经视网膜疾病联系起来的病理生理机制，我们比较了诊断为两种代谢交织疾病的患者：黄斑毛细血管扩张II型（MacTel）、遗传性感觉自主神经病变I型（HSAN 1）或两者。方法我们对来自MacTel（205）的队列的血清中的氨基酸和广义鞘脂进行了靶向代谢组学分析，HSAN 1（25）和控制（151）participators.ResultsMacTel患者表现出广泛的氨基酸的变化，包括丝氨酸，甘氨酸，丙氨酸，谷氨酸和支链氨基酸的变化，让人联想到糖尿病。MacTel患者循环中1-脱氧鞘脂升高，但复合鞘脂水平降低。视网膜病变的小鼠模型表明饮食丝氨酸和甘氨酸限制可以驱动复杂鞘脂的这种消耗。与对照组相比，HSAN 1患者表现出丝氨酸升高，丙氨酸降低，典型神经酰胺和鞘磷脂减少。那些被诊断为HSAN 1和MacTel的患者表现出最显着的减少循环sphingomyelins.ConclusionsThese结果突出MacTel和HSAN 1之间的代谢差异，强调MacTel的进展中的膜脂质的重要性，并建议不同的治疗方法，这两种神经退行性疾病。
ObjectivesThe 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.MethodsWe performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants.ResultsMacTel 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.ConclusionsThese 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.