Bielekova, B. | Search bioRxiv

bioRxiv2025

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

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 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.

neuroscience↗

bioRxiv2024

Apolipoprotein-L1 G1 variant contributes to hydrocephalus but not to atherosclerosis in apolipoprotein-E knock-out mice

IntroductionIn USA, six million individuals with Sub-Saharan ancestry carry two APOL1 high-risk variants, which increase the risk for kidney diseases. Whether APOL1 high-risk variants are independent risk factors for cardiovascular diseases is unclear and requires further investigation. MethodsWe characterized a mouse model to investigate the role of APOL1 in dyslipidemia and cardiovascular diseases. Transgenic mice carrying APOL1 (G0 and G1 variants) on bacterial artificial chromosomes (BAC/APOL1 mice) were crossed with the ApoE knock-out (ApoE-KO) atherosclerosis mouse model. The compound transgenic mice were evaluated for the impact of APOL1 on systemic phenotypes. ResultsApoE-KO mice carrying APOL1-G0 and APOL1-G1 did not show differences in the extent of atherosclerotic lesions or aortic calcification, as evaluated by Sudan IV staining and radiographic examination, respectively. However, [~]20% of ApoE-KO; BAC/APOL1-G1 mice developed hydrocephalus and required euthanasia. The hydrocephalus was communicating and likely was due to excess cerebrospinal fluid produced by the choroid plexus, where epithelial cells expressed APOL1. Single-nuclear RNA-seq of choroid plexus identified solute transporter upregulation and mTORC2 pathway activation in APOL1-G1-expressing epithelial cells. Further, in the All of Us cohort, we found higher hydrocephalus prevalence among individuals with the APOL1-G1 variant in both recessive and dominant models, supporting the mouse findings. ConclusionWhile APOL1-G1 expression in ApoE-KO mice did not worsen cardiovascular disease phenotypes, we uncovered hydrocephalus as a novel APOL1 risk allele-mediated phenotype. These findings extend the spectrum of APOL1-associated pathologies.

molecular biology↗