bims-meglyc 2026-09-06 papers

Issue of 2026–09–06
four papers selected by
Silvia Radenkovic, UMC Utrecht

PLoS Genet. 2026 Aug;22(8): e1012294

A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG.

Miriam C Aziz, Jennie Wilson, Clement Y Chow.

PIGA-CDG is a congenital disorder of glycosylation caused by pathogenic partial loss-of-function variants in the PIGA gene. PIGA encodes an enzyme responsible for the catalytic transfer of N-acetylglucosamine to phosphatidylinositol during the first step of glycosylphosphatidylinositol anchor biosynthesis. Loss of this enzyme has a widespread phenotypic impact, but primarily results in neurological symptoms including seizures, intellectual disability, and developmental delay. Currently, treatments are limited and focus on symptom management. We developed an eye model of PIGA-CDG that has a reduced eye size. We screened a library of 98% 1,520 FDA/EMA-approved compounds to find drugs that improved the small eye phenotype. This screen revealed numerous drugs that improved eye size, including those that targeted dopamine signaling and cyclooxygenases. Using pharmacological and genetic approaches, we show that modulating dopamine signaling improves the eye size. Genetic inhibition of dopamine 2 receptor signaling and dopamine reuptake improve both the eye model and neurologically relevant PIGA-CDG phenotypes, including seizures and locomotor deficits. We also pharmacologically and genetically validate cyclooxygenase targeting drugs in the eye model. These findings reveal novel biology underlying PIGA-CDG and point towards candidate therapeutic approaches.

DOI: https://doi.org/10.1371/journal.pgen.1012294

Methods Mol Biol. 2026 ;3020 287-300

Assay to Measure Scrambling of Dolichol-Linked Oligosaccharide in Reconstituted Vesicles.

Indu Menon, Anant K Menon.

The oligosaccharide needed for N-glycoprotein biosynthesis is assembled in two stages on the lipid carrier dolichyl phosphate. First, the key glycolipid intermediate Mannose5N-acetylglucosamine2-PP-dolichol (M5-DLO) is synthesized on the cytoplasmic face of the endoplasmic reticulum (ER). Next, M5-DLO is translocated (scrambled) across the ER membrane, where it is converted to mature DLO. Scrambling is facilitated by specific membrane proteins, some of which remain to be identified. Here, we describe an assay to measure scrambling of M5-DLO in synthetic phospholipid vesicles reconstituted with detergent-solubilized ER membrane proteins, or purified scramblase candidates. This assay will aid in the discovery and mechanistic characterization of M5-DLO scramblases.

Keywords: Dolichol; Endoplasmic reticulum; Glycolipid; Glycosylation; Liposome; Mannose; Oligosaccharide; Phospholipid; Reconstitution; Rft1; Scramblase; Triton X-100

DOI: https://doi.org/10.1007/978-1-0716-5186-5_15

Front Neurol. 2026 ;17 1878916

Glycosylation disorders in pediatric epilepsy: pathophysiology, imaging and precision therapy.

Lijuan Fan, Yajun Shen, Jianjun Wang, Jing Gan.

Epilepsy is a common neurological disorder in children and about 30% of children with epilepsy develop drug-resistant epilepsy. Epilepsy resulting from genetic variations and structural brain abnormalities has been extensively studied. Based on the current evidence, however, glycosylation, a major post-translational modification on over 70% of human brain proteins, is necessary for the stability of neural networks. This article delves into the many aspects of glycosylation abnormalities in epilepsy, including impairing early neural development, affecting the transport and function of ion channels, disrupting synaptic receptor and vesicular transport, and exacerbating neuroinflammatory damage. At the same time, the relationship between glycosylation and epilepsy is bidirectional. Glycosylation disorders induce seizures and chronic seizures induce a glycomic remodeling of the brain. This forms a vicious cycle and becomes a "background mechanism" of susceptibility and drug resistance for epilepsy. Specific and individualized approaches to clinical management must be adopted, including substrate supplementation, the ketogenic diet, and new specific drugs, such as enzyme inhibitors, pharmacological chaperones, and gene therapy. Future studies should focus on combining multi-omics data with high resolution neuroimaging to gain insights into the spatiotemporal dynamics of glycosylation abnormalities; the development of more targeted drugs according to the level of post-translational modification; and the formulation of more precise intervention strategies involving pediatric patients.

Keywords: epilepsy; excitation-inhibition balance; glycosylation disorders; neural network remodeling; precision therapy

DOI: https://doi.org/10.3389/fneur.2026.1878916

Mol Genet Metab. 2026 Aug 26. pii: S1096-7192(26)00531-7. [Epub ahead of print]149(1-2): 110248

Clinical and biochemical footprints of inherited disorders of autophagy.

Heinz Jungbluth, Hormos S Dafsari, Carlos R Ferreira, Nenad Blau.

Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.

Keywords: Autophagosome; Autophagy; Genomics; Inherited metabolism; Lysosome; Neurodegeneration; Neurodevelopment

DOI: https://doi.org/10.1016/j.ymgme.2026.110248