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Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2
Nathalie Escande-Beillard1, Abigail Loh2, Sahar N Saleem3
1Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore; Genome Institute of Singapore, A∗STAR, Singapore 138672, Singapore; Department of Medical Genetics, Koç University, School of Medicine, 34010 Istanbul, Turkey.
Abstract:
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.
Insights
Genetic mutations in PYCR2, an enzyme synthesizing proline, cause microcephaly. Loss of PYCR2 leads to excessive glycine in the brain, driving neurological symptoms, offering a potential therapeutic target.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Patients with PYCR2 deficiency exhibit microcephaly and hypomyelination.
- PYCR2 is a mitochondrial enzyme crucial for proline synthesis.
Purpose of the Study:
- To elucidate the structural and functional impact of PYCR2 mutations.
- To investigate the molecular mechanisms underlying PYCR2-associated neurological disorders.
- To identify potential therapeutic targets for PYCR2-mutant patients.
Main Methods:
- Determined the crystal structure of the PYCR2 apo-enzyme.
- Generated and analyzed Pycr2 knockout mice.
- Quantified neurotransmitters in mouse brains and patient samples.
- Investigated the role of SHMT2 in glycine synthesis.
Main Results:
- A novel mutation (p.Gly249Val) at the PYCR2 dimer interface reduces enzymatic activity.
- Pycr2 knockout mice models recapitulate human disease phenotypes.
- Excessive cerebral glycine and upregulated SHMT2 observed in PYCR2 deficiency.
- SHMT2 knockdown partially reversed neurological deficits in cultured neurons.
Conclusions:
- Loss of PYCR2 function leads to neurological impairment via glycine dysregulation.
- The glycine metabolic pathway, specifically SHMT2, is a potential therapeutic target.
- Understanding PYCR2's role offers insights into microcephaly and hypomyelination disorders.
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