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Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.
Bell, Scott; McCarty, Vincent; Peng, Huashan; Jefri, Malvin; Hettige, Nuwan; Antonyan, Lilit; Crapper, Liam; O'Leary, Liam A; Zhang, Xin; Zhang, Ying; Wu, Hanrong; Sutcliffe, Diane; Kolobova, Ilaria; Rosenberger, Thad A; Moquin, Luc; Gratton, Alain; Popic, Jelena; Gantois, Ilse; Stumpf, Patrick S; Schuppert, Andreas A; Mechawar, Naguib; Sonenberg, Nahum; Tremblay, Michel L; Jinnah, Hyder A; Ernst, Carl.
Afiliación
  • Bell S; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • McCarty V; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Peng H; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Jefri M; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Hettige N; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Antonyan L; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Crapper L; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • O'Leary LA; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Zhang X; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Zhang Y; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Wu H; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Sutcliffe D; Department of Neurology, Emory University, Atlanta, GA, USA; Department of Human Genetics, Emory University, Atlanta, GA, USA; Department of Pediatrics, Emory University, Atlanta, GA, USA.
  • Kolobova I; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Rosenberger TA; Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA.
  • Moquin L; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Gratton A; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Popic J; Department of Biochemistry, McGill University, Montreal, QC, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
  • Gantois I; Department of Biochemistry, McGill University, Montreal, QC, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
  • Stumpf PS; Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany.
  • Schuppert AA; Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany.
  • Mechawar N; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada.
  • Sonenberg N; Department of Biochemistry, McGill University, Montreal, QC, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
  • Tremblay ML; Department of Biochemistry, McGill University, Montreal, QC, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
  • Jinnah HA; Department of Neurology, Emory University, Atlanta, GA, USA; Department of Human Genetics, Emory University, Atlanta, GA, USA; Department of Pediatrics, Emory University, Atlanta, GA, USA.
  • Ernst C; Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada. Electronic address: carl.ernst@mcgill.ca.
Stem Cell Reports ; 16(7): 1749-1762, 2021 07 13.
Article en En | MEDLINE | ID: mdl-34214487
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Mesencéfalo / Metabolismo Energético / Neuronas Dopaminérgicas / Síndrome de Lesch-Nyhan Tipo de estudio: Etiology_studies Límite: Humans Idioma: En Revista: Stem Cell Reports Año: 2021 Tipo del documento: Article País de afiliación: Canadá

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Mesencéfalo / Metabolismo Energético / Neuronas Dopaminérgicas / Síndrome de Lesch-Nyhan Tipo de estudio: Etiology_studies Límite: Humans Idioma: En Revista: Stem Cell Reports Año: 2021 Tipo del documento: Article País de afiliación: Canadá