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The SORL1 gene encodes the sortilin-related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in SORL1 are causative for Alzheimer's disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains. SORL1 is highly expressed in the central nervous system, including in microglia, the tissue-resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia-like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to AD pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1–42 and synaptosomes is increased in SORLA-deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired in SORL1-deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in the proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo-lysosomal network as a potential novel pathway through which SORL1 may increase AD risk and contribute to the development of AD. Additionally, our findings may inform the development of novel lysosome and microglia-associated drug targets for AD.

The mammalian suprachiasmatic nucleus (SCN) orchestrates daily (circadian) rhythms of physiology and behavior by broadcasting timing cues generated autonomously by its mutually reinforcing network of ~10,000 neurons and ~3000 astrocytes. Although astrocytic control of extracellular glutamate and GABA has been implicated in driving circadian oscillations in SCN gene expression and neuronal activity, the full scale of the network-level signaling mechanisms is unknown. To understand better how this astrocyte-neuron network operates, we adopted a multi-omics approach, first using SILAC-based mass spectrometry to generate an SCN proteome where ~7% of identified proteins were circadian. This circadian proteome was analyzed bioinformatically alongside existing single-cell RNAseq transcriptomic data to identify the cell-types and processes to which they contribute. This highlighted “S100 protein binding,” tracked to astrocytes, and revealed annexin-A2 (Anxa2) as an astrocyte-enriched circadian protein for further investigation. We show that Anxa2 and its partner S100a10 are co-expressed and enriched in SCN astrocytes. We also show that pharmacological disruption of their association acutely and reversibly dysregulated the circadian cycle of astrocytic calcium levels and progressively compromised SCN neuronal oscillations. Anxa2 and S100a10 interaction therefore constitutes an astrocytic cellular signaling axis that regulates circadian neuronal excitability and ultimately SCN network coherence necessary for circadian timekeeping.

Astrocytes in the retina and optic nerve head play an important role in the pathogenesis of glaucoma. Astrocytes extensively express connexin 43 (Cx43), a protein that forms gap junction (GJ) channels and transmembrane unopposed hemichannels. While it is well documented that Cx43 expression is augmented in retinal injuries, the role of astrocytic Cx43 channels in glaucomatous injury is not fully understood. Here, we used a mouse model of ocular hypertension caused by intracameral microbead injections and a more severe model, optic nerve crush (ONC) injury, and assessed changes in Cx43 expression and GJ channel function. The effect of astrocyte-specific deletion of Cx43 (Cx43KO) on retinal ganglion cell (RGC) loss and visual function was also assessed. We show that the Cx43 expression is increased in retinal astrocytes at early time points and remained elevated even after sustained elevation of intraocular pressure (IOP) (~8 weeks), which paralleled an increase in astrocytic GJ coupling. Deletion of astrocytic Cx43 markedly improved the survival of RGCs by ~93% and preserved visual function as assessed by ERG and reduced numbers of activated microglial/macrophages in the glaucomatous retina. Cx43 expression was also substantially increased after ONC injury, and the absence of Cx43 in this model increased RGC survival by ~48%. These results reveal a deleterious role for Cx43 in glaucoma progression. Intravitreal injections of Gap19, a peptide that reportedly inhibits Cx43 hemichannels but not GJ channels, markedly increased RGC survival and visual function. Further studies are required to assess whether targeting Cx43 hemichannels might be useful for glaucoma treatment.

Individual protoplasmic astrocytes have very complex and diverse spongiform shapes. The morphological diversity of astrocytes is determined by the structural and functional interactions of the astrocyte with its microenvironment. When faced with pathological conditions, astrocytes reorganize their morphology. Yet, little is known about the astrocytic response in pure tauopathies and its evolution over time. Here, we aimed to investigate the consequences of a primary neuronal tau pathology on astrocyte fine morphology at three stages of the disease using the transgenic Thy-Tau22 mouse model. We first showed that hippocampal astrocytes in Thy-Tau22 mice progressively accumulate hyperphosphorylated tau with age. We then developed a pipeline of analyses, including 3D reconstruction of hippocampal tdTomato-labeled astrocytes via a PHP.eB adeno-associated virus, confocal microscopy, Imaris software morphometric analysis, and an advanced statistical analysis. During normal aging, the complexity of astrocyte morphology peaked at adulthood, then declined. In contrast, in Thy-Tau22 mice, tauopathy was associated with a simpler initial morphology, followed by the appearance of a cluster of complex cells at the most advanced stage. Using principal component analysis and hierarchical clustering based on 10 morphological features, we were able to identify different astrocyte morphotypes whose relative proportion varies differently with age between WT and Thy-Tau22 mice. Interestingly, we revealed that a fraction of astrocytes with a complex morphology re-emerges late in tauopathy-affected animals. Our data highlight the concept of significant and reversible structural plasticity of astrocytes when faced with chronic pathological conditions.

The aging central nervous system (CNS) is often marked by myelin degeneration, yet the underlying mechanisms remain elusive. This study delves into the previously unexplored role of autophagy in maintaining CNS myelin during aging. We generated the transgenic mouse line plpCre ^ERT2 ; atg5 ^f/f , enabling selective deletion of the core autophagic component Atg5 in oligodendrocytes (OLs) following tamoxifen administration in adulthood, while analysis was conducted on aged mice. Our findings reveal that oligodendroglial autophagy inactivation leads to significant alterations in myelin protein levels. Moreover, the ultrastructural analysis revealed pronounced myelin deficits and increased degeneration of axons, accompanied by apoptosis, as confirmed by immunohistochemistry. Behaviorally, aged knockout (cKO) mice exhibited marked deficits in learning and memory tasks, indicative of cognitive impairment. Additionally, we observed increased activation of microglia, suggesting an inflammatory response linked to the absence of autophagic activity in OLs. These results underscore the critical role of autophagy in OLs for the preservation of CNS myelin and axonal integrity during aging. Our study highlights autophagy as a vital mechanism for neural maintenance, offering potential therapeutic avenues for combating age-related neurodegenerative diseases.

COASY protein-associated neurodegeneration (CoPAN) is a rare autosomal recessive disorder within the Neurodegeneration with Brain Iron Accumulation spectrum, resulting from mutations in COASY. This gene encodes the bifunctional enzyme essential for the final steps of coenzyme A biosynthesis. To elucidate the pathophysiology and iron dyshomeostasis underlying CoPAN, we analyzed fibroblasts and human induced pluripotent stem (hiPS)-derived astrocytes from two patients carrying distinct COASY mutations. Our findings reveal that CoPAN fibroblasts display altered iron homeostasis, characterized by iron aggregates, elevated cytosolic labile iron pool, and impaired tubulin acetylation. Patients hiPS-derived astrocytes showed mitochondrial morphological abnormalities and compromised vesicular trafficking. Notably, both cell types demonstrated evidence of ferroptosis, but the astrocytes exhibited more pronounced iron accumulation and lipid peroxidation. These results demonstrate that astrocytes may more accurately recapitulate the pathological phenotype of CoPAN compared to fibroblasts. Interestingly, astrocytes exhibited different levels of iron accumulation concomitant with cellular senescence, indicating a possible role of iron-induced cellular senescence. This finding suggests that the accumulation of cytosolic iron, possibly caused by mitochondrial dysfunction, actively promotes senescence. Our data emphasize the potential therapeutic efficacy of drugs that enhance mitochondrial functionality to attenuate the effects of CoPAN.

Two percent of patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a concurrent disruption in white matter integrity. In this study, we demonstrate that deletion of Zdhhc9 in mice disrupts the balance of mature oligodendrocyte subtypes within the corpus callosum. While overall mature oligodendrocyte numbers are unchanged, there is a marked increase in MOL5/6 cells that are enriched in genes associated with cell adhesion and synapses, and a concomitant decrease in MOL2/3 cells that are enriched in genes associated with myelination. In line with this, we observed a decrease in the density of myelinated axons and disruptions in myelin compaction in the corpus callosum of Zdhhc9 knockout mice. RNA sequencing and proteomic analysis further revealed a reduction in genes and proteins essential for lipid metabolism, cholesterol synthesis, gene expression, and myelin compaction, offering insights into the underlying mechanisms of the pathology. These findings reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte subtype determination and myelinogenesis, offering mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.