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

ABSTRACT: Genetic mutations affecting proteasome function can result in multi-organ diseases, such as Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. Neurological symptoms associated with CANDLE suggest that proteasomal mutations may impact neuronal development and/or function. We generated cerebral organoids (COs) from CANDLE patient induced pluripotent stem cells (iPSCs), which exhibited impaired neuronal development when compared to COs from healthy control iPSCs. Impaired neuronal maturation in CANDLE COs was correlated with increased polyamines, which were also elevated in CANDLE patient CSF. The proteasome-regulated Ornithine decarboxylase (ODC), a rate limiting enzyme for polyamines, was elevated in CANDLE neurons. Inhibition of ODC reve

SUBMITTER: Winkler CW 

PROVIDER: S-EPMC12393280 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature