ArticleNature communications2024
The hexosamine biosynthetic pathway rescues lysosomal dysfunction in Parkinson's disease patient iPSC derived midbrain neurons.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Targeting ROAM1 with UDP-GlcNAc nanosheets selective activates lysosomal AMPK to resolve metabolic dysfunction-associated steatotic liver disease.Bioactive materials · 2026Article
- Glutamine metabolism in health and disease.Signal transduction and targeted therapy · 2026Review
- GFPT2 promotes macrophage dysfunction in atherosclerosis via ACADL glycosylation-dependent suppression of ACADL and Arg1.Cellular and molecular life sciences : CMLS · 2026Article
- Myosin-actin pattern links matrix stiffness to GFAT2-hyaluronan metabolism.Materials today. Bio · 2025Article
- Abnormal glycosylation changes in brain tissue of kainic acid-induced epileptic rats.Scientific reports · 2025Article
- Phosphoproteomic insights into GFPT2-Associated cellular phospho-signaling networks.Biochemistry and biophysics reports · 2025Article
- Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes.Molecular neurodegeneration · 2025Article
- Parkinson's disease and glucose metabolism impairment.Translational neurodegeneration · 2025Review
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Authors and funding
4 authors.
Funding
Abstract
Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson's disease, however their mechanistic linkage is largely unexplored. The hexosamine biosynthetic pathway utilizes glucose and uridine-5'-triphosphate to generate N-linked glycans required for protein folding in the endoplasmic reticulum. Here we find that Parkinson's patient midbrain cultures accumulate glucose and uridine-5'-triphosphate, while N-glycan synthesis rates are reduced. Impaired glucose flux occurred by selective reduction of the rate-limiting enzyme, GFPT2, through disrupted signaling between the unfolded protein response and the hexosamine pathway. Failure of the unfolded protein response and reduced N-glycosylation caused immature lysosomal hydrolases to misfold and accumulate, while accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein. Our data indicate that the hexosamine pathway integrates glucose metabolism with lysosomal activity, and its failure in Parkinson's disease occurs by uncoupling of the unfolded protein response-hexosamine pathway axis. These findings offer new methods to restore proteostasis by hexosamine pathway enhancement.
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