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.
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Article Synopsis
- The final step of proline biosynthesis involves three enzymes, PYCR1, PYCR2, and PYCR3, which convert a compound called pyrroline-5-carboxylate into proline, with mutations in these genes linked to specific human diseases like Cutis Laxa and hypomyelinating leukodystrophy.
- Research on mouse models revealed that Pycr1 mutations did not lead to any notable skin-related problems, whereas Pycr2 mutations resulted in neurological and neuromuscular symptoms, though peripheral nerves were mostly unaffected.
- Both PYCR1 and PYCR2 show overlapping functions in proline metabolism, reinforcing that while they can compensate for each other's absence, a deficiency in either disrupts pro
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