Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2

Nathalie Escande-Beillard, Abigail Loh, Sahar N. Saleem, Kohei Kanata, Yui Hashimoto, Umut Altunoglu, Artina Metoska, Joanes Grandjean, Fui Mee Ng, Oz Pomp, Nithya Baburajendran, Joyner Wong, Jeffrey Hill, Emmanuel Beillard, Patrick Cozzone, Maha Zaki, Hülya Kayserili, Hiroshi Hamada, Hidetaka Shiratori, Bruno Reversade

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.
Original languageEnglish (US)
Pages (from-to)82-94.e6
Number of pages93999919
Issue number1
StatePublished - Jul 8 2020
Externally publishedYes

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Generated from Scopus record by KAUST IRTS on 2023-02-15


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