An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology

Author(s): Sheehan, PW; Nadarajah, CJ; Kanan, MF; Patterson, JN; Novotny, B; Lawrence, JH; King, MW; Brase, L; Inman, CE; Yuede, CM; Lee, J; Patel, TK; Harari, O; Benitez, BA; Davis, AA; Musiek, ES;
Year: 2023;  
Journal: Neuron;  
Volume: 111;  
Issue: 15;  

The circadian clock protein BMAL1 modulates glial activation and amyloid-beta deposition in mice. However, the effects of BMAL1 on other aspects of neurodegenerative pathology are unknown. Here, we show that global post-natal deletion of Bmal1 in mouse tauopathy or alpha-synucleinopathy models unexpectedly suppresses both tau and alpha-synuclein (αSyn) aggregation and related pathology. Astrocyte-specific Bmal1 deletion is sufficient to prevent both αSyn and tau pathology in vivo and induces astrocyte activation and the expression of Bag3, a chaperone critical for macroautophagy. Astrocyte Bmal1 deletion enhances phagocytosis of αSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression is sufficient to mitigate αSyn spreading in vivo. In humans, BAG3 is increased in patients with AD and is highly expressed in disease-associated astrocytes (DAAs). Our results suggest that early activation of astrocytes via Bmal1 deletion induces Bag3 to protect against tau and αSyn pathologies, providing new insights into astrocyte-specific therapies for neurodegeneration.