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

Willayat Y. Wani, Friederike Zunke, Nandkishore R. Belur and Joseph R. Mazzulli ()
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Willayat Y. Wani: Northwestern University Feinberg School of Medicine
Friederike Zunke: Northwestern University Feinberg School of Medicine
Nandkishore R. Belur: Northwestern University Feinberg School of Medicine
Joseph R. Mazzulli: Northwestern University Feinberg School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49256-3

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