Proteasome mutations associated with CANDLE syndrome cause altered neuronal development by dysregulating polyamine synthesis
Clayton W. Winkler, Benjamin Schwarz, Katie Williams, Sara Alehashemi, Simote T. Foliaki, Joseph Snow, Lisa Joseph, Audrey Thurm, Christopher L. Friend, Gwendolyn Cooper, Eric Bohrnsen, Farzana Bhuyan, Nathan T. Brandes, Ruin Moaddel, Manfred Boehm, Guibin Chen, Cole D. Kimzey, Bibiana Bielekova, Joanna Kocot, Peter Kosa, Cathryn L. Haigh, Raphaela Goldbach-Mansky, Karin E. Peterson
Clayton W. Winkler, Benjamin Schwarz, Katie Williams, Sara Alehashemi, Simote T. Foliaki, Joseph Snow, Lisa Joseph, Audrey Thurm, Christopher L. Friend, Gwendolyn Cooper, Eric Bohrnsen, Farzana Bhuyan, Nathan T. Brandes, Ruin Moaddel, Manfred Boehm, Guibin Chen, Cole D. Kimzey, Bibiana Bielekova, Joanna Kocot, Peter Kosa, Cathryn L. Haigh, Raphaela Goldbach-Mansky, Karin E. Peterson
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Research Article Genetics Metabolism Neuroscience

Proteasome mutations associated with CANDLE syndrome cause altered neuronal development by dysregulating polyamine synthesis

Abstract

Loss-of-function mutations in PSMB8/β5i and other components of the 20S proteasome result in multiorgan diseases, such as Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. Neurocognitive dysfunction associated with CANDLE suggests that proteasomal mutations may impact neuronal function and development early in life. We generated cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) made from patients with CANDLE. The COs from CANDLE iPSCs exhibited impaired neuronal development when compared with COs from healthy control iPSCs. Impaired neuronal maturation in CANDLE COs was correlated with increased polyamines, which were also elevated in CSF from patients with CANDLE. The proteasome-regulated ornithine decarboxylase (ODC), the rate limiting enzyme in polyamine biosynthesis, was elevated in CANDLE neurons. Inhibition of ODC reversed polyamine overproduction and repaired neuronal maturation in CANDLE COs, suggesting a potential therapeutic avenue for intervention. These findings demonstrate that dysfunction of the proteasome affects neuronal development through overproduction of polyamines via dysregulation of ODC and offer insight into potential therapeutic strategies for CNS-related proteasomal dysfunction.

Authors

Clayton W. Winkler, Benjamin Schwarz, Katie Williams, Sara Alehashemi, Simote T. Foliaki, Joseph Snow, Lisa Joseph, Audrey Thurm, Christopher L. Friend, Gwendolyn Cooper, Eric Bohrnsen, Farzana Bhuyan, Nathan T. Brandes, Ruin Moaddel, Manfred Boehm, Guibin Chen, Cole D. Kimzey, Bibiana Bielekova, Joanna Kocot, Peter Kosa, Cathryn L. Haigh, Raphaela Goldbach-Mansky, Karin E. Peterson

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Figure 5

CSF from patients with CANDLE have altered polyamine, nucleobase, and Acetyl-CoA metabolism.

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CSF from patients with CANDLE have altered polyamine, nucleobase, and Ac...
(A) A comparison of CANDLE versus HC CSF metabolites via t test (biological: n = 3 CANDLE, n = 7 HC). Metabolites annotated as being associated with amine metabolism, Acetyl-CoA metabolism, and nucleobase metabolism are highlighted. Lines representing the raw P value cutoff for an FDR of 10 % or 20 % calculated via a Benjamini Hochberg correction are indicated. (B) Amine metabolism map of the same metabolite data and comparison displayed in A with the fold change of metabolites represented as color and the significance represented as node size as indicated in the legend. Hatch marked nodes indicate metabolites below the limit of detection. Patient CSF data for (C) amine, (D) nucleobase, and (E) Acetyl-CoA metabolites that passed an FDR 20 % cutoff are shown for each individual patient or control. Data are plotted in z-scale using the variance of all samples to normalize the distribution for comparison purposes. The range, quartiles, and median are indicated by box and whiskers. An unpaired t test was used to compare between CANDLE and HC and the Benjamini-Hochberg corrected P value is displayed above each comparison.