bims-meglyc 2025-10-26 papers

Issue of 2025–10–26
four papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2025 Oct 15. pii: S1096-7192(25)00248-3. [Epub ahead of print]146(3): 109256

Letter to the editors: Supervised machine learning prediction of genotype-phenotype correlations in PMM2-CDG, in response to Pajusalu et al. [].

Julia Boonnak.

Keywords: Artificial intelligence; Binding site mutations; Congenital disorders of glycosylation; Genotype-phenotype correlation; PMM2-CDG; Pathogenicity prediction

DOI: https://doi.org/10.1016/j.ymgme.2025.109256

J Inherit Metab Dis. 2025 Nov;48(6): e70109

ATP6AP2 splicing variants cause syndromic X-linked intellectual disability Hedera type (XPDS; OMIM#300423) and X-linked parkinsonism with spasticity (MRXSH; OMIM#300911). Alternatively, ATP6AP2 missense variants lead to hepatopathy, immunological abnormalities, cutis laxa and only mild intellectual disability with N-/O-glycosylation defects (ATP6AP2-CDG; OMIM#301045). The disparity between neurological and hepatic ATP6AP2-related disease entities is an ongoing puzzle. We aimed to investigate whether patients with an isolated neurological presentation of ATP6AP2-related disease, consistent with XPDS/MRXSH, also have abnormal glycosylation biomarkers, potentially implicating this as part of the pathological mechanism. We identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. We describe defective glycosylation alongside ATP6AP2 splicing variants in four patients, including the first female with ATP6AP2-related disease. This connects more closely the phenotypes of XPDS/MRXSH and ATP6AP2-CDG and indicates that abnormal glycosylation markers may be a consistent feature of splicing variants, and potentially part of the pathological mechanism underlying ATP6AP2-related disease caused by abnormal splicing. We also provide additional evidence that neurodevelopment is uniquely sensitive to the gene dosage of ATP6AP2, linked to the isolated neurological phenotype found in patients with splice variants and the attenuated, but still severe, phenotype of the female in our study. Glycosylation defects can be found in "splicing" forms of ATP6AP2-related diseases, bridging the gap between XPDS, MRXSH and ATP6AP2-CDG.

Keywords: ATP6AP2; CDG; Golgi V‐ATPase; MRXSH; XPDS

DOI: https://doi.org/10.1002/jimd.70109

FASEB J. 2025 Oct 31. 39(20): e71160

Decoding Glycosylation in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Opportunities.

Haihan Yu, Xing Chen, Yang Yang, Mengke Gu, Kaidi Ren, Ziqing Wei.

Glycosylation is a highly dynamic and complex post-translational modification that plays a pivotal role in regulating protein folding, trafficking, stability, and function. Accumulating evidence indicates that aberrant glycosylation is intimately involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review provides a comprehensive overview of the molecular mechanisms by which the two predominant forms of glycosylation, N-glycosylation and O-GlcNAcylation, contribute to protein misfolding, synaptic dysfunction, neuroinflammation, and impaired stress responses in the diseased nervous system. We further explore the diagnostic potential of glycosylation biomarkers and emerging therapeutic strategies targeting glycosylation pathways. Special emphasis has been placed on recent advances in glycomic technologies, artificial intelligence-driven analytics, and nanocarrier-based drug delivery platforms. By integrating mechanistic insights with translational applications, this review highlights glycosylation as both a pathological driver and a promising therapeutic target in neurodegenerative disorders.

Keywords: glycosylation; neurodegenerative diseases; neuroinflammation; post‐translational modification; therapeutic strategies

DOI: https://doi.org/10.1096/fj.202502809R

Adv Biol Regul. 2025 Oct 10. pii: S2212-4926(25)00047-8. [Epub ahead of print] 101120

OGT's inner circle: Protein interactions and functional impact.

Fiddia Zahra, Natasha E Zachara.

The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as an essential post-translational modification in mammals. More than 5000 human proteins are subject to O-GlcNAcylation, influencing key cellular processes such as signal transduction, epigenetic regulation, transcription, translation, and bioenergetics. Dysregulation of this modification has been implicated in a wide range of diseases, including metabolic disorders, cancer, neurodegeneration, ischemic injury, and heart failure. O-GlcNAc-cycling is orchestrated by two enzymes: the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and removal of O-GlcNAc, respectively. A central challenge in the field is understanding how this minimal enzymatic machinery achieves such broad substrate specificity. It is hypothesized that OGT's functional versatility is mediated through interactions with a diverse network of protein partners that act as adaptors, scaffolds, or substrates, thereby directing its localization, modulating its activity, and shaping its substrate selectivity. In this review, we discuss key interactors and their functional impact on OGT. We also explore how post-translational modifications and substrate availability contribute to OGT regulation and specificity.

Keywords: Glycosylation; Interactome; Intracellular; O-GlcNAc; O-GlcNAc transferase; Signaling; UDP-GlcNAc

DOI: https://doi.org/10.1016/j.jbior.2025.101120