Absence of BBSome function leads to astrocyte reactivity in the brain

Abstract

In humans, dysfunctional primary cilia result in Bardet-Biedl syndrome (BBS), which presents with clinical features including intellectual disabilities, obesity, and retinal degeneration, and, in mouse models, the added feature of hydrocephalus. We observed increased Glial Fibrillary Acidic Protein (GFAP) immunoreactivity in BBS mouse brains. Increased GFAP expression is a hallmark of astrocyte reactivity that is associated with microglia activation and neuro-inflammation. To gain a better understanding of reactive astrocytes observed in BBS mice, we used two mouse models of BBS8, a BBSome protein, to characterize the reactive astrocyte phenotype. The finding of reactive astrocytes in young BBS mouse brains led us to hypothesize that loss of BBSome function leads to reactive astrocytes prior to hydrocephalus and obesity. By using two mouse models of BBS8, a congenital BBS8 knockout with hydrocephalus, and a tamoxifen-inducible BBS8 knockout without hydrocephalus, we were able to molecularly phenotype the reactive astrocytes. Molecular phenotype of reactive astrocytes shows differential regulation of inducers of Pan, A1 neurotoxic, and A2 neuroprotective astrocytes that are significantly altered in brains of both congenital and induced knockouts of BBS8, but without microglia activation. We find evidence for neuroinflammation in the brains of congenital knockout mice, but not in induced knockout mice. Protein levels of GFAP, SERPINA3N and post-synaptic density 95 (PSD95) are significantly increased in congenital knockout mice, but remain unchanged in induced knockout mice. Thus, despite the reactive astrocyte phenotype being present in both models, the molecular signature of reactive astrocytes in BBS8 mice models are distinct. Together, these findings suggest that BBS8, and by extension the BBSome, plays a role in neuro-astrocyte functions independent of hydrocephalus, and its dysregulation is associated with astrocyte reactivity without microglia activation. (Total word count 278).

SerpinA3N attenuates ischemic stroke injury by reducing apoptosis and neuroinflammation

“…Consistent with previous study 1 , we found that serpinA3N expression was upregulated at 6-12 h after reperfusion and lasted for This was controversial with the previous belief that serpinA3N was a marker of reactive astrocytes 1 . Although most reported the expression of serpinA3N in reactive astrocytes in various models, 14,15,41 two recent studies revealed serpinA3N expression in neurons in schizophrenia model 42 and in oligodendrocytes in Alzheimer's disease (AD). 43 We are the first to report serpinA3N cellular distribution in stroke model.…”

Loss of the Reissner Fiber and increased URP neuropeptide signaling underlie scoliosis in a zebrafish ciliopathy mutant

“…Cilia defects can trigger inflammation in the kidney and in the brain [34,35]. Moreover, Urotensin II signaling induces inflammation in many contexts [36], raising the interesting possibility that increased URP signaling from CSF-cNs could drive neuroinflammation in the rpgrip1l ∆/∆ zebrafish scoliosis model.…”

A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment

“…In order to control for these phenotypes, we used young adult mice prior to the onset of obesity and blindness. In addition, our BBS1 conditional knockout mice are not blind nor obese and BBS8 conditional knockout mice do not have hydrocephalus [ 20 , 51 ], yet both models have impaired long-term context fear conditioning. We were not able to account for the olfactory deficit as a confounding factor.…”