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

Author

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  • Willayat Y. Wani

    (Northwestern University Feinberg School of Medicine)

  • Friederike Zunke

    (Northwestern University Feinberg School of Medicine
    Friedrich-Alexander University Erlangen-Nürnberg)

  • Nandkishore R. Belur

    (Northwestern University Feinberg School of Medicine)

  • Joseph R. Mazzulli

    (Northwestern University Feinberg School of Medicine)

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.

Suggested Citation

  • Willayat Y. Wani & Friederike Zunke & Nandkishore R. Belur & Joseph R. Mazzulli, 2024. "The hexosamine biosynthetic pathway rescues lysosomal dysfunction in Parkinson’s disease patient iPSC derived midbrain neurons," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49256-3
    DOI: 10.1038/s41467-024-49256-3
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    References listed on IDEAS

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    1. Sonja Kriks & Jae-Won Shim & Jinghua Piao & Yosif M. Ganat & Dustin R. Wakeman & Zhong Xie & Luis Carrillo-Reid & Gordon Auyeung & Chris Antonacci & Amanda Buch & Lichuan Yang & M. Flint Beal & D. Jam, 2011. "Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease," Nature, Nature, vol. 480(7378), pages 547-551, December.
    2. Haik Mkhikian & Ani Grigorian & Carey F. Li & Hung-Lin Chen & Barbara Newton & Raymond W. Zhou & Christine Beeton & Sevan Torossian & Gevork Grikor Tatarian & Sung-Uk Lee & Ken Lau & Erin Walker & Kat, 2011. "Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis," Nature Communications, Nature, vol. 2(1), pages 1-13, September.
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