Convergent cerebrospinal fluid proteomes and metabolic ontologies in humans and animal models of Rett syndrome

Zlatic, Stephanie A.; Duong, Duc; Gadalla, Kamal K.E.; Murage, Brenda; Ping, Lingyan; Shah, Ruth; Fink, James J.; Khwaja, Omar; Swanson, Lindsay C.; Şahin, Mustafa; Rayaprolu, Sruti; Kumar, Prateek; Rangaraju, Srikant; Bird, Adrian; Tarquinio, Daniel; Carpenter, Randall L.; Cobb, Stuart; Faúndez, Víctor

doi:10.1016/j.isci.2022.104966

Cited by 5 publications

(6 citation statements)

References 91 publications

(109 reference statements)

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“…S3B). Of note, Serpina1e protein levels were previously reported to be reduced levels in the CSF of Mecp2 mutant mice (Zlatic et al, 2022). Genetic defects in Mecp2 cause widespread non-overlapping modifications of the transcriptome and proteome across tissues.…”

Section: Resultsmentioning

confidence: 93%

“…We previously demonstrated that decreased mitochondrial respiration in mutant LUHMES cells can be restored by reintroduction of the MECP2 gene (Zlatic et al, 2022). Similar gene re-expression experiments were performed in HAP1 cells.…”

Section: Resultsmentioning

confidence: 99%

“…For example, Mecp2 defective cholesterol synthesis pathways in liver have a parallel in brain where de novo synthesis of cholesterol is diminished (Buchovecky et al, 2013). Brain and liver defects in cholesterol synthesis may be linked to changes in the content of HDL lipoproteins in the cerebrospinal fluid of Mecp2 mutant animal and neuronal models as well as in Mecp2 tm1.1Bird/y mouse plasma (unpublished results) (Zlatic et al, 2022). These findings suggest that a plasma biomarker assessing a Rett syndrome liver phenotype has potential to correlate with similar processes in brain.…”

Section: Discussionmentioning

confidence: 96%

“…Aacs encodes a acetoacetyl-CoA synthetase that takes acetyl-CoA to funnel it to the cholesterol synthesis pathway (Ohgami et al, 2003). The hypothesis that a pyruvate-acetyl-CoA axis is regulated by the Mecp2 protein is supported by the results in cerebrospinal fluid from Mecp2-null mouse documenting changes in the levels of mitochondrial factors that metabolize pyruvate (Zlatic et al, 2022). Mecp2 deficiency has also been reported to decrease levels of pyruvate dehydrogenase E1 subunit beta, and levels of this subunit are restored when Mecp2 is re-expressed (Cortelazzo et al, 2020).…”

Section: Discussionmentioning

confidence: 98%

“…Confidence in the validity of our analyses is further increased by the robustness of the replication despite considerable differences in methodology including a different Mecp2 animal model, timing and method of tissue collection, the mass spectrometry strategy, and data processing between our study and those employed for the whole isocortex proteome (Pacheco et al, 2017). Furthermore, the ontological/pathway similarity of the mouse brain Mecp2 cortex proteome extends to the mouse and rat cerebrospinal Mecp2 mutant proteomes demonstrating robustness in pathway identification in Mecp2 mutant brain (Zlatic et al, 2022). Our data suggest that the poor correlation between the Mecp2 -sensitive brain transcriptomes and proteomes may be disease phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants

Zlatic

Werner

Surapaneni

et al. 2023

Preprint

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Neurodevelopmental disorder genes are broadly expressed supporting the concept that these disorders are systemic diseases that impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice and MECP2-null human cells were assessed. Widespread changes in the transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice and mutant cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants

Zlatic

Werner

Surapaneni

et al. 2023

Preprint

Self Cite

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Analysis of the interplay between MeCP2 and histone H1 during in vitro differentiation of human ReNCell neural progenitor cells

Siqueira,

Kim,

Reser

et al. 2023

Epigenetics

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Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants

Zlatic,

Werner,

Surapaneni

et al. 2023

Human Molecular Genetics

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Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

show abstract

Convergent cerebrospinal fluid proteomes and metabolic ontologies in humans and animal models of Rett syndrome

Cited by 5 publications

References 91 publications

Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants

Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants

Analysis of the interplay between MeCP2 and histone H1 during in vitro differentiation of human ReNCell neural progenitor cells

Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants

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