Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2
| Autor: | Hiroshi Hamada, Bruno Reversade, Artina Metoska, Fui Mee Ng, Jeffrey Hill, Patrick Cozzone, Nithya Baburajendran, Hülya Kayserili, Oz Pomp, Nathalie Escande-Beillard, Joyner Wong, Abigail Loh, Kohei Kanata, Sahar N. Saleem, Joanes Grandjean, Yui Hashimoto, E. Beillard, Umut Altunoglu, Hidetaka Shiratori, Maha S. Zaki |
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| Přispěvatelé: | ACS - Heart failure & arrhythmias |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Microcephaly MRS Adolescent Neurite hypomyelination Mutant Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] Glycine medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans mouse models microcephaly Cerebral Cortex Glycine Hydroxymethyltransferase Mice Knockout Phenocopy Mutation Gene knockdown Chemistry General Neuroscience Neurodegeneration neurodegeneration Infant medicine.disease SHMT2 PYCR1 Pedigree Cell biology PYCR2 Hereditary Central Nervous System Demyelinating Diseases cerebral glycine 030104 developmental biology Child Preschool Nerve Degeneration Female Pyrroline Carboxylate Reductases 030217 neurology & neurosurgery HLD10 |
| Zdroj: | Neuron, 107, 82-94 e6 Neuron, 107(1), 82-94.e6. Cell Press Neuron, 107, 1, pp. 82-94 e6 |
| ISSN: | 0896-6273 |
| Popis: | Patients lacking PYCR2, a mitochondrial enzyme that synthesizes proline, display postnatal degenerative microcephaly with hypomyelination. Here we report the crystal structure of the PYCR2 apo-enzyme and show that a novel germline p.Gly249Val mutation lies at the dimer interface and lowers its enzymatic activity. We find that knocking out Pycr2 in mice phenocopies the human disorder and depletes PYCR1 levels in neural lineages. In situ quantification of neurotransmitters in the brains of PYCR2 mutant mice and patients revealed a signature of encephalopathy driven by excessive cerebral glycine. Mechanistically, we demonstrate that loss of PYCR2 upregulates SHMT2, which is responsible for glycine synthesis. This hyperglycemia could be partially reversed by SHMT2 knockdown, which rescued the axonal beading and neurite lengths of cultured Pycr2 knockout neurons. Our findings identify the glycine metabolic pathway as a possible intervention point to alleviate the neurological symptoms of PYCR2-mutant patients. Escande-Beillard et al. establish a mouse model of PYCR2 inactivation that phenocopies human neurodegenerative disease (HLD10). Metabolomic and functional analyses in mutant mice and patients reveal that cerebral hyperglycinemia is a driver of the disease, which can be corrected by inhibiting SHMT2. |
| Databáze: | OpenAIRE |
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