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

• Published in: Nature communications Vol. 15; no. 1; pp. 5206 - 17
• Main Authors: Wani, Willayat Y., Zunke, Friederike, Belur, Nandkishore R., Mazzulli, Joseph R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-06-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 14; 38; 38/88; 631/378; 631/378/1689/1718; 631/378/1689/364; 82/29; 96; 96/106; Age; alpha-Synuclein - metabolism; Biosynthetic Pathways; Endoplasmic reticulum; Fluctuations; Glucose; Glucose - metabolism; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - genetics; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - metabolism; Glycan; Glycosylation; Hexosamines - biosynthesis; Hexosamines - metabolism; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Lysosomes - metabolism; Mesencephalon; Mesencephalon - metabolism; Metabolism; multidisciplinary; N-glycans; Neurodegenerative diseases; Neurons; Neurons - metabolism; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Polysaccharides; Protein folding; Protein turnover; Proteins; Science; Science (multidisciplinary); Synuclein; Unfolded Protein Response; Uridine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49256-3

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.
Reduced glucose flux via the hexosamine pathway contributes to lysosomal dysfunction and protein accumulation in Parkinson patient iPSC-neurons. Enhancing the hexosamine pathway rescues lysosome activity and restores proteostasis.