Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.

TitleLesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.
Publication TypeJournal Article
Year of Publication2021
AuthorsBell 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
JournalStem Cell Reports
Volume16
Issue7
Pagination1749-1762
Date Published2021 07 13
ISSN2213-6711
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.

DOI10.1016/j.stemcr.2021.06.003
Alternate JournalStem Cell Reports
PubMed ID34214487
PubMed Central IDPMC8282463
Grant ListR01 NS109242 / NS / NINDS NIH HHS / United States
R56 NS102980 / NS / NINDS NIH HHS / United States
/ / CIHR / Canada