bims-meglyc 2026-08-30 papers

Issue of 2026–08–30
four papers selected by
Silvia Radenkovic, UMC Utrecht

J Cell Biochem. 2026 Aug;127(8): e70119

Impacts of N-glycanase1 (NGLY1) Down Regulation on the Function of Mitochondria.

Yanwen Chen, Ruijie Liu, Shaoxing Zhang, Yuxin Zhang, Qiange Lin, Yilin Ye, Shuying Yuan, Xinrong Lu, Linfei Wang, Li Chen, Guiqin Sun.

N-glycanase 1 (NGLY1) is involved in intracellular misfolded protein degradation, releasing a de-N-glycosylated protein and a complete N-oligosaccharide. Enzymatic defects in NGLY1 may cause NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG). NGLY1 patients exhibit cognition and coordination defects, and the regulatory impact of NGLY1 in the organism deserves in-depth investigation. In this study, we established NGLY1-knockdown human foreskin fibroblasts-1 (HFF-1) cells and observed mitochondrial function impairments. We conservatively suggest that NGLY1 has global regulatory roles within cells. The Calnexin/IP3R/VDAC1 axis acts as a communication bridge and represents one mechanism underlying NGLY1-mediated modulation of mitochondrial function. This has significant implications for addressing the clinical disease problems presented by NGLY1-CDDG.

Keywords: NGLY1; N‐glycanase 1; deglycosylation; mitochondria; molecular mechanism

DOI: https://doi.org/10.1002/jcb.70119

Case Rep Neurol. 2026 Jan-Dec;18(1):18(1): 506-513

Asymmetric Distal-Onset GNE Myopathy Mimicking Peripheral Neuropathy: A Case Report.

Dipta Chandra Kuri, Sadeka Afrin Losy, Mohammad Sadekur Rahman Sarkar, Md Badrul Alam Mondal.

Introduction: GNE myopathy is a rare autosomal recessive distal myopathy classically characterized by symmetrical distal muscle weakness with relative quadriceps sparing. However, phenotypic variability, including asymmetric onset, may obscure the diagnosis and mimic neuropathic disorders.
Case Presentation: A 27-year-old Bangladeshi man presented with a 2-year history of progressive distal weakness, initially involving the left lower limb and later affecting the contralateral limb and distal upper extremities. Neurological examination revealed asymmetric distal weakness with bilateral foot drop and preserved sensory function. Serum creatine kinase was moderately elevated (892 U/L). Nerve conduction studies showed preserved sensory responses with reduced motor amplitudes, while electromyography demonstrated a distal-predominant myopathic pattern. Magnetic resonance imaging of the spine was unremarkable. Clinical exome sequencing identified a homozygous likely pathogenic variant in the GNE gene NM_005476.7:c.484C>T (p.Arg162Cys), confirming the diagnosis.
Conclusion: This case highlights an asymmetric presentation of GNE myopathy mimicking peripheral neuropathy. Recognition of such phenotypic variability and integration of clinical, electrophysiological, and genetic findings are crucial for accurate diagnosis and to avoid misclassification as a neuropathic disorder.

Keywords: Distal myopathies; Electromyography; Exome sequencing; Foot drop; GNE myopathy; Muscle weakness; Peripheral neuropathy

DOI: https://doi.org/10.1159/000553628

J Inherit Metab Dis. 2026 Sep;49(5): e70245

A Contemporary Pathomechanistic Nosology of Inherited Lysosomal Disorders.

Eamon P McCarron, Nenad Blau, Emily R Eden, Frances M Platt, Johannes M Aerts, Simon A Jones, Carlos R Ferreira, Karolina M Stepien.

Lysosomal disorders (LDs) have traditionally been defined by intra-lysosomal substrate accumulation resulting from deficiencies of lysosomal enzymes or associated proteins. Advances in lysosomal biology have demonstrated that lysosomes function as central regulators of cellular signalling, membrane trafficking, autophagy, nutrient sensing, organelle communication and cellular homeostasis, expanding the spectrum of inherited disorders associated with lysosomal dysfunction beyond classical storage phenotypes. We developed a contemporary pathomechanistic nosology of inherited LDs through expert curation and targeted review of databases and published literature. Disorders were included when pathogenic variants resulted in lysosomal dysfunction as a major disease mechanism through defects affecting lysosomal degradation, membrane function, intracellular trafficking, biogenesis, autophagy-lysosome pathways or lysosome-related organelles. A total of 108 inherited lysosomal disorders caused by defects in 102 genes were identified and organised into 11 major disease categories. Neurologic and eye involvement were the most frequently affected organ-system categories, occurring in 80.6% and 68.5% of disorders, respectively. Digestive (including hepatosplenomegaly), dysmorphic, skeletal and haematological involvement occurred in 48.1%, 45.4%, 40.7% and 38.9% of disorders, respectively. Distinct phenotypic signatures were observed across disease categories despite substantial mechanistic overlap involving impaired autophagy, vesicular trafficking, lysosomal stress and altered organelle homeostasis. This proposed nosology extends disease classification beyond substrate accumulation alone and provides a biologically informed framework for disease classification, genomic interpretation, biomarker development, patient stratification and the development of mechanism-based therapies.

Keywords: autophagy; disease classification; endolysosomal pathway; inherited lysosomal disorders; inherited metabolic disorders; lysosomal storage disorders; lysosome; nosology

DOI: https://doi.org/10.1002/jimd.70245

Curr Opin Chem Biol. 2026 Aug 28. pii: S1367-5931(26)00106-7. [Epub ahead of print]94 102757

Chemical biology tools for the O-GlcNAc modification: Determining systems-level functions and druggability.

Charlie Fehl.

How can a single monosaccharide control nearly every human cellular feature? This question has hounded the O-GlcNAc field since 1984. Despite identifying thousands of O-GlcNAc proteins, high-throughput datasets have only deepened the mystery. This Current Opinion highlights chemical biology tools (current as of 2023-2026) that reveal coordinated O-GlcNAc networks in physiology and disease. We review five areas: (1) systems-level maps of tissue-specific OGT interactomes and substrates; (2) spatiotemporal tools for precise glycosylation manipulation; (3) multiplexed detection assays for O-GlcNAc activities alongside other PTMs; (4) targeted modulation via nontraditional inhibitors, noncatalytic OGT scaffolding, and ligand-directed assembly; and (5) disease models uncovering tissue-specific effects. Recent OGA inhibitor clinical challenges in Phase 1 and 2 studies pose existential questions about drugging O-GlcNAc, but recent advances covered in this Opinion propose insights for safe therapeutic targeting. Through the lens of new chemical biology tools, we see detailed patterns in how nutrient-responsive O-GlcNAcylation subtly regulates cellular decision-making.

DOI: https://doi.org/10.1016/j.cbpa.2026.102757