Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.
Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.
复制标题
DOI：
10.1016/j.stemcr.2021.06.003
复制
发表时间：
2021-07-13
影响因子：
5.9
通讯作者：
Ernst C
中科院分区：
文献类型：
--
作者：
Bell S;McCarty V;Peng H;Jefri M;Hettige N;Antonyan L;Crapper L;O'Leary LA;Zhang X;Zhang Y;Wu H;Sutcliffe D;Kolobova I;Rosenberger TA;Moquin L;Gratton A;Popic J;Gantois I;Stumpf PS;Schuppert AA;Mechawar N;Sonenberg N;Tremblay ML;Jinnah HA;Ernst C
HPRT 1基因突变可导致Lesch-Nyhan病，其特征是自我损伤和运动障碍。HPRT 1基因编码嘌呤补救的限速酶。我们利用干细胞和基因工程技术在同基因和患者来源的前脑和中脑细胞类型中模拟疾病。多巴胺能祖细胞缺乏HPRT显示所有发育细胞命运标记物的强度下降。代谢分析显示，所有嘌呤衍生物的显着损失，除了次黄嘌呤，受损的糖酵解和氧化磷酸化。实时葡萄糖示踪显示，以ATP产生为代价，增加了向磷酸戊糖途径的分流，以从头合成嘌呤。多巴胺能祖细胞中嘌呤耗竭导致RHEB丧失，损害mTORC 1活化。这些数据证明了嘌呤补救缺陷的多巴胺能特异性作用，并且出乎意料地揭示了多巴胺能祖细胞在终末分化细胞的更高能量需求之前被编程为高能量状态。HPRT 1 KO降低NPC和神经元中细胞命运标记物的表达与皮质NPC相比，NPC具有程序化的高能量状态HPRT 1 KO NPC优先考虑从头嘌呤合成而不是能量产生HPRT 1 KO NPC具有降低的RHEB和mTORC 1活化水平Ernst和同事显示了细胞命运标记物的神经元细胞类型特异性效应和来自HPRT缺陷细胞的氧化磷酸化能力，提供了对Lesch-Nyhan病神经学特征的机制性见解。
Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells. HPRT1 KO reduces cell-fate marker expression in NPCs and neurons NPCs have a programmed high-energy state compared with cortical NPCs HPRT1 KO NPCs prioritize de novo purine synthesis over energy production HPRT1 KO NPCs have reduced levels of RHEB and mTORC1 activation Ernst and colleagues show neuronal cell-type-specific effects of cell-fate markers and oxidative phosphorylation capacity from HPRT-deficient cells, providing mechanistic insight into the neurological features of Lesch-Nyhan disease.
登录
查看更多内容
影响因子：
5.2
作者：
Cork GK;Thompson J;Slawson C
通讯作者：
Slawson C
影响因子：
4.7
作者：
EDELSTEIN, SB;CASTIGLIONE, CM;BREAKEFIELD, XO
通讯作者：
BREAKEFIELD, XO
影响因子：
16.2
作者：
HYNES, M;PORTER, JA;ROSENTHAL, A
通讯作者：
ROSENTHAL, A
影响因子：
4.8
作者：
Biever A;Valjent E;Puighermanal E
通讯作者：
Puighermanal E
影响因子：
4.3
作者：
Jinnah, H. A.
通讯作者：
Jinnah, H. A.