Absence of BBSome function leads to astrocyte reactivity in the brain

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Dysfunctional primary cilia cause Bardet-Biedl syndrome (BBS) in humans, with symptoms like intellectual disability, obesity, and retinal degeneration.
• Mouse models of BBS exhibit hydrocephalus and increased Glial Fibrillary Acidic Protein (GFAP) immunoreactivity, indicating astrocyte reactivity and potential neuroinflammation.
• Astrocyte reactivity, marked by GFAP expression, is often linked to microglia activation and neuroinflammation, but its specific role in BBS pathogenesis is unclear.

Purpose of the Study:

• To investigate the role of BBSome protein BBS8 in reactive astrocyte phenotypes in mouse models.
• To determine if BBS8 loss leads to reactive astrocytes before the onset of hydrocephalus and obesity.
• To molecularly characterize reactive astrocytes in BBS8 knockout models with and without hydrocephalus.

Main Methods:

• Utilized two mouse models of BBS8: a congenital knockout with hydrocephalus and a tamoxifen-inducible knockout without hydrocephalus.
• Performed molecular phenotyping of reactive astrocytes in both BBS8 mouse models.
• Assessed protein levels of GFAP, SERPINA3N, and post-synaptic density 95 (PSD95) in the brains of knockout mice.

Main Results:

• Reactive astrocytes were observed in young BBS8 mouse brains, supporting the hypothesis that BBSome dysfunction precedes hydrocephalus and obesity.
• Molecular phenotyping revealed differential regulation of astrocyte states (Pan, A1, A2) in both congenital and inducible BBS8 knockouts, independent of microglia activation.
• Congenital BBS8 knockout mice showed increased GFAP, SERPINA3N, and PSD95 with evidence of neuroinflammation, while inducible knockout mice did not exhibit these changes, indicating distinct molecular signatures.

Conclusions:

• BBS8, and the BBSome complex, play a role in neuro-astrocyte function independently of hydrocephalus.
• Dysregulation of BBS8 is associated with astrocyte reactivity without concurrent microglia activation.
• The distinct molecular signatures of reactive astrocytes in BBS8 models highlight the complexity of BBS pathogenesis and potential therapeutic targets.