The hexosamine biosynthetic pathway rescues lysosomal dysfunction in Parkinson's disease patient iPSC derived midbrain neurons.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Hexosamines*/biosynthesis ; Hexosamines*/metabolism ; Lysosomes*/metabolism ; Parkinson Disease*/metabolism ; Parkinson Disease*/pathology ; Unfolded Protein Response* ; Neurons*/metabolism ; Induced Pluripotent Stem Cells*/metabolism ; Mesencephalon*/metabolism ; Glucose*/metabolism ; Biosynthetic Pathways*; Humans ; Glycosylation ; alpha-Synuclein/metabolism ; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/metabolism ; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/genetics

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.
(© 2024. The Author(s).)

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P30 AG013854 United States AG NIA NIH HHS; R01 NS092823 United States NS NINDS NIH HHS; R01NS092823 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); P30 AG062677 United States AG NIA NIH HHS; P01 AG003949 United States AG NIA NIH HHS; MJFF-021532 Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)

0 (Hexosamines)
IY9XDZ35W2 (Glucose)
0 (alpha-Synuclein)
EC 2.6.1.16 (Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing))

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240622

20240622

PMC11186828

10.1038/s41467-024-49256-3

38897986