Miguel, L. | bioRxiv Science

bioRxiv2026

Persistent cerebrovascular injury after preeclampsia in the STOX1A mouse model: implications for prokineticin signaling

Preeclampsia (PE) is a pregnancy-related hypertensive disorder associated with neurological complications that may persist beyond pregnancy. Prokineticins (PROK1 and PROK2) and their receptors (PROKR1 and PROKR2) regulate angiogenesis and inflammation and may be involved to PE-associated cerebrovascular injury. This study investigated alterations of the maternal brain prokineticin system during PE and 8 months postpartum, and assessed the consequences of prokineticin receptor inhibition using the PROKR antagonist PC1. Female WT FVB/N mice mated with transgenic males overexpressing STOX1A were used as a model of PE and received PC1 or vehicle during gestation. Circulating and regional brain PROK levels and receptor expression were assessed by ELISA and Western blotting. Long-term cerebral abnormalities were evaluated using high-resolution MRI and GFAP immunostaining. PE mice exhibited hypertension, proteinuria, reduced placental efficiency, and elevated circulating PROK1 and PROK2 levels. PC1 prevented hypertension and attenuated the elevation of circulating PROKs but did not prevent proteinuria or reduced placental efficiency. During PE, hippocampal PROK1 increased while PROK2 decreased; these changes persisted despite treatment. At 7 months postpartum, both PROKs were elevated in the cortex, and these increases were prevented by PC1. Region-specific changes in PROKR1 immunoreactivity and PROKR2 expression showed variable responses to treatment. MRI revealed hippocampal and parieto-temporal T2* hypointensities compatible with microhemorrhagic injury, post-contrast T1 abnormalities supporting blood-brain barrier disruption, and a distinct caudoputamen T1-hyperintense lesion potentially representing a nonhemorrhagic component. PC1 prevented focal cerebral lesions and associated astrocyte reactivity, whereas regional diffusion abnormalities persisted. These findings implicate prokineticin signaling in persistent PE-associated brain injury and support the potential of receptor antagonism to limit selected cerebral alterations.

neuroscience↗

bioRxiv2021

Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimers disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of A{beta} peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 71 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variations (R332W, S577P, and R654W) and two maturation-competent variations (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of A{beta} secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variations on SorLA protein indicated that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

cell biology↗