bims-meglyc 2026-03-15 papers

Issue of 2026–03–15
four papers selected by
Silvia Radenkovic, UMC Utrecht

Nat Chem Biol. 2026 Mar 10.

Structures of ALG3/9/12 reveal the assembly logic of the N-glycan oligomannose core.

J Andrew N Alexander, Shu-Yu Chen, Somnath Mukherjee, Mario de Capitani, Rossitza N Irobalieva, Lorenzo Rossi, Parth Agrawal, Julia Kowal, Matheus A Meirelles, Markus Aebi, Jean-Louis Reymond, Anthony A Kossiakoff, Sereina Riniker, Kaspar P Locher.

Asparagine-linked glycans are essential for the maturation and function of most eukaryotic secretory proteins. The biosynthesis and transfer of dolichylpyrophosphate-anchored GlcNAc2Man9Glc3 glycan is a highly conserved process occurring in the endoplasmic reticulum (ER) membrane and involving over a dozen membrane proteins whose dysfunction is linked to congenital disorders of glycosylation (CDGs). Three membrane-integral mannosyltransferases, ALG3, ALG9 and ALG12, mediate four consecutive mannosylation reactions that convert GlcNAc2Man5 to GlcNAc2Man9. Here, using chemoenzymatically synthesized lipid-linked glycan donor and acceptor analogs, we recapitulated this biosynthetic pathway in vitro. High-resolution cryo-electron microscopy structures of pseudo-Michaelis complexes of each step revealed how the branched glycan is accurately synthesized and unwanted side products are averted. Molecular dynamics simulations and mutagenesis studies uncovered a subtle but precise mechanism selecting the dolichylphosphomannose donor substrate over dolichylphosphoglucose, which is also present in the ER membrane. Our results also provide mechanistic explanations for enzyme dysfunction in CDGs and offer opportunities for N-glycan engineering.

DOI: https://doi.org/10.1038/s41589-026-02164-7

Neuromolecular Med. 2026 Mar 09. pii: 16. [Epub ahead of print]28(1):

B4Galnt1 Deficiency Reverses Severe Neurological Symptoms in a Mouse Model of Tay-Sachs Disease.

Selman Yanbul, Tufan Utku Calıskan, Mustafa Can Turali, Volkan Seyrantepe.

Keywords: B4Galnt1; Ganglioside; Knockout mice; Tay-Sachs disease

DOI: https://doi.org/10.1007/s12017-026-08916-x

PLoS Genet. 2026 Mar;22(3): e1012076

COG5 deficiency disrupts cellular copper homeostasis and underlies the impaired mitochondrial OXPHOS function.

Yuwei Zhou, Keyi Li, Ruowei Zhu, Xue Ma, Xinfei Ye, Mengqing Mao, Ding Li, Xiaofei Zeng, Zhehui Chen, Jing Wu, Liqin Jin, Xiaohua Tang, Yanling Yang, Jianxin Lyu, Xiaoting Lou.

COG5, a subunit of the conserved oligomeric Golgi (COG) complex, plays a critical role in retrograde trafficking within the Golgi apparatus. Dysfunction of COG5 is associated with various human disorders, yet the underlying pathogenic mechanisms remain poorly understood. To investigate the mechanisms, we conducted proteomic analyses using COG5-deficient and rescue cell models, which revealed a potential link between COG5 dysfunction and mitochondrial oxidative phosphorylation (OXPHOS) deficiency. Using COG5-deficient cell models and patient-derived cells harboring COG5 variants, we biochemically validated the involvement of COG5 in mitochondrial OXPHOS, particularly in the regulation of complex I content. These models also exhibited elevated cellular copper levels. Notably, the significant reduction in OXPHOS complexes could be rescued by either restoring COG5 expression or administering a copper chelator. We further demonstrated that excessive cellular copper disrupts the function of mitochondrial iron-sulfur clusters, potentially leading to complex I assembly defects. Additionally, we identified a patient with biallelic COG5 variants presenting with a distinct subtype of mitochondrial disease (Leigh syndrome), a phenotype not previously associated with COG5-related disorders. These findings provide novel mechanistic insights into the role of COG5, extending beyond its established function in Golgi-mediated glycosylation modifications. Our results underscore the importance of COG5 in mitochondrial function through a copper-dependent pathway, offering new perspectives on its contribution to cellular homeostasis and disease pathogenesis.

DOI: https://doi.org/10.1371/journal.pgen.1012076

Neurochem Int. 2026 Mar 10. pii: S0197-0186(26)00037-9. [Epub ahead of print] 106146

Human Neuraminidase 3 reduces the severity of Tay-Sachs disease symptoms in a mouse model.

Hande Basırlı, Volkan Seyrantepe.

Tay-Sachs disease (TSD) is a neurodegenerative disorder caused by mutations in the HEXA gene, encoding the α-subunit of β-hexosaminidase A. HexA deficiency leads to impaired degradation and accumulation of GM2 ganglioside, causing progressive neurodegeneration in patients. Interestingly, Hexa-/- mice show a relatively mild phenotype, suggesting degradation of stored GM2 ganglioside through a 'bypass' involving a sialidase. To investigate whether sialidase Neu3 contributes to GM2 degradation, mice deficient in both HEXA and NEU3, Hexa-/-Neu3-/-, were generated. Abnormal GM2 accumulation was revealed in the brains of Hexa-/-Neu3-/- mice using thin-layer chromatography and mass spectrometric analyses. Immunohistological and histological analyses indicated astrogliosis, Purkinje cell loss, and progressive neurodegeneration. Furthermore, the mice exhibited marked neurological abnormalities, including slowed movement, ataxia, and tremors, as well as a shortened lifespan of approximately 20 weeks. Hence, Hexa-/-Neu3-/- mice, which mimic the neuropathological and clinical abnormalities observed in patients, were considered the early-onset TSD model. The role of endogenous human Neu3 in GM2 degradation remains unknown. To evaluate its therapeutic potential, we administered AAVrh10-hNeu3 intrathecally to 8-week-old Hexa-/-Neu3-/- mice, either alone or with an anti-inflammatory agent, Istradefylline. Treatment with human Neu3 and Istradefylline extended lifespan to 28 weeks, improved body weight, and reduced GM2 accumulation. Additionally, fewer lysosomal LAMP1- and TUNEL-positive cells, and higher CNPase levels were revealed. Rotarod and footprint analyses showed improvements at 20 weeks. Our results provide the first in vivo evidence that AAV-mediated human Neu3 expression and Istradefylline may slow disease progression, reduce neuropathology, and lessen motor deficits in the Hexa-/-Neu3-/- mouse model of TSD.

Keywords: AAV-based gene therapy; Intrathecal delivery; Istradefylline; Neuraminidase Neu3; Tay-Sachs disease

DOI: https://doi.org/10.1016/j.neuint.2026.106146