Alzheimer's and Parkinson's disease are progressive neurodegenerative disorders of the central nervous system for which there is currently no cure. Although both diseases have distinct clinical features causing either primarily cognitive or motor impairments, they are based on the misfolding and aggregation of proteins such as β-amyloid, p-tau or α-synuclein. Understanding the mechanisms of protein homeostasis is therefore crucial to minimize misfolded protein aggregates and reduce or reverse clinical symptoms.
Several lines of evidence suggest that tau and synuclein pathologies are associated with pronounced microglial and astrocyte activation. Whether astrocyte activation is protective or detrimental to disease progression is currently the subject of intense debate. While studies show that reducing astrocyte reactivity by inhibiting Na/K-ATPase can be protective for the development of tauopathies, more recent findings suggest that reactive astrocytes can also have a protective effect by inducing proteostasis via the JAK2-STAT3 axis.
One mechanism that regulates cell-autonomous astrocyte reactivity is the circadian molecular transcription factor BMAL1. Disturbances of sleep and circadian rhythm are common in Alzheimer's and Parkinson's disease and can precede disease manifestation. BMAL1 acts as a transcriptional regulator of astrocytes and its disruption leads to specific changes in these cells. However, it remains unclear whether the astrocyte reactivity induced by BMAL1 deletion is protective or detrimental to the course of neurodegenerative pathologies.
In a study published last year in Neuron, Sheehan, Nadarajah and colleagues used two well-established mouse models that lead to the aggregation of misfolded proteins: the P301S tau transgene mouse model and a model for α-synuclein pathology in which preformed synuclein fibrils are injected into the brain. By deleting Bmal1 in these mice either globally or in glia, the authors investigated the role of BMAL1-dependent glial reactivity in the development of tau and synuclein pathologies.
The results show that deleting Bmal1 in astrocytes reduces protein aggregation, while deleting it in microglia had no comparable effects. Remarkably, astrocyte-specific deletion of Bmal1 facilitates the phagocytosis of misfolded proteins via the upregulation of BAG3. BAG3 is a chaperone involved in macroautophagy and supports the degradation of protein aggregates. These effects were demonstrated both in vitro and in vivo. Further analyses of human brain tissue and databases showed that BAG3 is upregulated in astrocytes of Alzheimer's patients in the late stages of the disease. In addition, a genetic variation in an open chromatin region of astrocytes was associated with an increased risk of Parkinson's disease.
Together, the results suggest that the BMAL1-BAG3 axis may play a preventive role in the development of neurodegenerative diseases by promoting the clearance of protein aggregates. This opens up promising opportunities for the development of targeted therapies that target astrocyte reactivity and protein homeostasis, particularly in early disease stages.
References:
Rojo D, Gibson EM (2023) Timing matters: A protective role of astrocyte reactivity in neurodegeneration. Neuron 111:2277-2279.
Sheehan PW, Nadarajah CJ, Kanan MF, ... , Benitez BA, Davis AA, Musiek ES (2023) An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology. Neuron 111:2383
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