Bertran-Cobo, C. | bioRxiv Science

bioRxiv2025

Maternal and child immune profiles are associated with neurometabolite measures of early-life neuroinflammation in children who are HIV-exposed and uninfected: a South African birth cohort

Children who are HIV-exposed and uninfected (HEU) are at risk of neurodevelopmental delays, which may be partially due to maternal immune dysregulation during pregnancy. This study investigates associations between maternal and child immune profiles and early neurometabolite profiles in HEU and HIV-unexposed (HU) children from a South African birth cohort. A subgroup of 156 children (66 HEU, 90 HU) from the Drakenstein Child Health Study underwent magnetic resonance spectroscopy at age 2-3 years, and maternal and child serum markers were measured at multiple timepoints via immunoassays. In HEU children, serum concentrations of maternal pro-inflammatory cytokines IL-5 ({beta}=0.79, p=0.005) and IL-8 ({beta}=0.64, p=0.02) were associated with myo-inositol ratios in parietal grey and white matter regions, respectively, while child serum MMP-9 at two years was associated with myo-inositol ratios in the midline parietal grey matter ({beta}=1.30, p=0.03). The association of maternal anti-inflammatory cytokine IL-13 with glutamate ratios in the midline parietal grey matter was negative in HEU ({beta}=-0.41, p=0.038) and positive in HU children ({beta}=0.42, p<0.0001). These findings suggest maternal immune activation may affect neurometabolite profiles in HEU children.

neuroscience↗

bioRxiv2023

Altered TFEB subcellular localization in nigral dopaminergic neurons of subjects with prodromal, sporadic and GBA-related Parkinson's disease and Dementia with Lewy bodies

Transcription factor EB is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinsons disease (PD) and dementia with Lewy bodies (DLB). TFEB activation at the lysosomal level results in its translocation from the cytosol to the nucleus. Here, we aimed at investigating whether TFEB subcellular localization is altered in post-mortem human brain of aged individuals with either prodromal PD/DLB (incidental Lewy body disease, iLBD, N=3), GBA-related PD/DLB (N=9) or sPD/DLB (N=9), compared to control subjects (N=12). We scanned nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the observed TFEB subcellular localization patterns. In line with previous studies, we observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn cytopathology and in cases carrying pathogenic GBA variants. Interestingly, we further observed previously unidentified TFEB-immunopositive somatic clusters in human brain dopaminergic neurons and in human embryonic stem cell (hESC)-derived neurons, which localized at the Golgi apparatus. The TFEB clustering was more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons but also in neurons without apparent cytopathology. Notably, increased frequency of cytoplasmic TFEB clusters in aSyn-negative cells correlated with reduced total GBA enzymatic activity and higher Braak LB stage. In the studied patient population, altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected CLEAR genes, indicating a possible early dysfunction of lysosomal regulation. Overall, these findings suggest the early cytoplasmic TFEB retention and accumulation at the Golgi prior pSer129 aSyn accumulation in incidental, GBA-related and sporadic PD/DLB and indicate TFEB as potential as early therapeutic target for synucleinopathies

neuroscience↗