| First Author | Sheehan PW | Year | 2023 |
| Journal | Neuron | Volume | 111 |
| Issue | 15 | Pages | 2383-2398.e7 |
| PubMed ID | 37315555 | Mgi Jnum | J:339356 |
| Mgi Id | MGI:7518168 | Doi | 10.1016/j.neuron.2023.05.006 |
| Citation | Sheehan PW, et al. (2023) An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology. Neuron 111(15):2383-2398.e7 |
| abstractText | 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 (alphaSyn) aggregation and related pathology. Astrocyte-specific Bmal1 deletion is sufficient to prevent both alphaSyn 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 alphaSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression is sufficient to mitigate alphaSyn 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 alphaSyn pathologies, providing new insights into astrocyte-specific therapies for neurodegeneration. |
