Circadian clock protein BMAL1 broadly influences autophagy and endolysosomal function in astrocytes

Abstract

An emerging role for the circadian clock in autophagy and lysosome function has opened new avenues for exploration in the field of neurodegeneration. The daily rhythms of circadian clock proteins may coordinate gene expression programs involved not only in daily rhythms but in many cellular processes. In the brain, astrocytes are critical for sensing and responding to extracellular cues to support neurons. The core clock protein BMAL1 serves as the primary positive circadian transcriptional regulator and its depletion in astrocytes not only disrupts circadian function but also leads to a unique cell-autonomous activation phenotype. We report here that astrocyte-specific deletion of Bmal1 influences endolysosome function, autophagy, and protein degradation dynamics. In vitro, Bmal1 -deficient astrocytes exhibit increased endocytosis, lysosome-dependent protein cleavage, and accumulation of LAMP1- and RAB7-positive organelles. In vivo, astrocyte-specific Bmal1 knockout (aKO) brains show accumulation of autophagosome-like structures within astrocytes by electron microscopy. Transcriptional analysis of isolated astrocytes from young and aged Bmal1 aKO mice indicates broad dysregulation of pathways involved in lysosome function which occur independently of TFEB activation. Since a clear link has been established between neurodegeneration and endolysosome dysfunction over the course of aging, this work implicates BMAL1 as a key regulator of these crucial astrocyte functions in health and disease.

Circadian Biology and the Neurovascular Unit

“…Bmal1 deletion in astrocytes leads to astrogliosis, with increased reactivity, autophagy/lysosomal degradation, and phagocytosis. 82,83 Rev-erbα-deficient microglia have a more variable response. There is increased reactivity, lipid droplet formation, and synaptic/Aβ phagocytosis; however, there is less extracellular Tau phagocytosis.…”

“…72 Bmal1 -deficient astrocytes show increased expression of lysosomal proteins and enhanced endocytosis in vitro. 82 Systemically, deleting Bmal1 in astrocytes causes metabolic imbalance, disrupted glutamate and GABA levels, and decreased life span. 88 In mouse models of tau and alpha-synuclein proteinopathy, astrocyte-specific Bmal1 deletion can increase macroautophagy and mitigate toxic protein aggregation (Figure 2).…”

“…B, Deletion of the core molecular clock proteins BMAL1 (basic helix-loop-helix Arnt [aryl hydrocarbon receptor nuclear translocator]-like protein 1) or REV-ERBα (reverse-ErbA-related receptor alpha) induce morphological and functional changes in glial cells**. Bmal1 deletion in astrocytes leads to astrogliosis, with increased reactivity, autophagy/lysosomal degradation, and phagocytosis 82,83. Rev-erbα-deficient microglia have a more variable response.…”

Circadian Mechanisms in Brain Fluid Biology

“…124 In the SCN, rhythms in astrocyte function regulate excitatory glutamatergic signaling 124,125 and inhibitory GABAergic signaling, 126,127 ultimately altering cellular metabolism and glucose homeostasis throughout the body. 127,128 Beyond the SCN, loss of BMAL1 in astrocytes leads to reactive gliosis, endosomal dysfunction, and altered homeostasis of amyloid-β within the CSF, 129–132 and astrocytes may undergo daily morphological changes. 133 Apart from genetic models of circadian clock disruption, the primary evidence for astrocytic regulation of circadian rhythms comes from studies of astrocytes in sleep.…”

Role of astrocytes in sleep deprivation: accomplices, resisters, or bystanders?

“…Recent studies have linked BMAL1 to protein degradation in astrocytes within the brain. McKee et al (2023) demonstrated that deleting Bmal1, specifically in astrocytes, leads to a unique cell-autonomous activation state. This activation phenotype not only disrupts circadian function but also hampers the supportive role of astrocytes to neurons while simultaneously increasing extracellular protein degradation ( McKee et al, 2023 ).…”