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Published on: April 14, 2017
Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models
Silvia Radenkovic1, Rohit Budhraja2, Teun Klein-Gunnewiek3
1Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
Abstract:
Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a rare inborn error of metabolism caused by deficiency of the PMM2 enzyme, which leads to impaired protein glycosylation. While the disorder presents with primarily neurological symptoms, there is limited knowledge about the specific brain-related changes caused by PMM2 deficiency. Here, we demonstrate aberrant neural activity in 2D neuronal networks from PMM2-CDG individuals. Utilizing multi-omics datasets from 3D human cortical organoids (hCOs) derived from PMM2-CDG individuals, we identify widespread decreases in protein glycosylation, highlighting impaired glycosylation as a key pathological feature of PMM2-CDG, as well as impaired mitochondrial structure and abnormal glucose metabolism in PMM2-deficient hCOs, indicating disturbances in energy metabolism. Correlation between PMM2 enzymatic activity in hCOs and symptom severity suggests that the level of PMM2 enzyme function directly influences neurological manifestations. These findings enhance our understanding of specific brain-related perturbations associated with PMM2-CDG, offering insights into the underlying mechanisms and potential directions for therapeutic interventions.
Insights
Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) causes neurological issues due to PMM2 enzyme deficiency. This study reveals impaired brain cell activity, mitochondrial dysfunction, and altered metabolism in PMM2-CDG, linking enzyme levels to symptom severity.
Area of Science:
- Biochemistry
- Neuroscience
- Metabolic Disorders
Background:
- Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a rare metabolic disorder.
- It stems from PMM2 enzyme deficiency, impairing protein glycosylation.
- Neurological symptoms are primary, but brain-specific changes are poorly understood.
Purpose of the Study:
- To investigate the specific brain-related alterations in PMM2-CDG.
- To elucidate the molecular mechanisms underlying neurological dysfunction in PMM2-CDG.
- To explore the relationship between PMM2 enzyme activity and disease severity.
Main Methods:
- Analysis of 2D neuronal networks from PMM2-CDG patients.
- Multi-omics analysis of 3D human cortical organoids (hCOs) from PMM2-CDG individuals.
- Assessment of protein glycosylation, mitochondrial structure, and glucose metabolism.
Main Results:
- Aberrant neural activity observed in 2D neuronal networks.
- Widespread decrease in protein glycosylation confirmed as a key pathological feature.
- Impaired mitochondrial structure and abnormal glucose metabolism identified in hCOs, indicating energy metabolism disturbances.
- Correlation found between PMM2 enzymatic activity in hCOs and neurological symptom severity.
Conclusions:
- PMM2 deficiency leads to significant brain-related perturbations, including impaired neural activity and energy metabolism.
- The findings highlight disturbed protein glycosylation and mitochondrial function as central to PMM2-CDG neuropathology.
- Enzyme activity levels directly correlate with neurological symptom severity, suggesting a basis for therapeutic strategies.
