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SYK coordinates neuroprotective microglial responses in neurodegenerative disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE212310 | GEO | 2022/10/15

REPOSITORIES: GEO

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SYK coordinates neuroprotective microglial responses in neurodegenerative disease.

Project description:Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer's disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material.

| S-EPMC9617784 | biostudies-literature

SYK coordinates neuroprotective microglial responses in neurodegenerative disease [scRNA-seq]

Project description:Many neurodegenerative diseases are thought to be caused by impaired containment and/or disposal of neurotoxic material such as amyloid beta (Ab) and myelin debris. Indeed, recent human genome-wide association studies (GWAS) and animal model studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, as well as various innate immune receptors expressed by microglia in the control of neurotoxic material and subsequent neurodegenerative disease pathogenesis. Yet, the critical intracellular molecules that orchestrate the neuroprotective functions of microglia in degenerative disorders remain poorly understood. In our studies, we have identified the innate immune signaling molecule spleen tyrosine kinase (SYK) as a key regulator of microglial phagocytosis in neurodegenerative disease. We find that targeted deletion of SYK in microglia leads to exacerbated Ab deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Furthermore, disruption of SYK signaling in this AD model was also shown to impede the development of disease-associated microglia (DAMs), alter AKT/GSK3b-signaling in microglia, and to cause severe deficits in the ability of microglia to phagocytose Ab. Importantly, these critical neuroprotective functions of SYK in microglia were not only restricted to Ab-driven models of neurodegeneration, as we found that SYK is also a critical regulator of microglial phagocytosis and DAM phenotype acquisition in demyelinating disease. Collectively, these results help to break new ground in our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material. Moreover, these findings suggest that targeting SYK may offer a therapeutic strategy to treat a spectrum of neurodegenerative disorders.

2022-10-15 | GSE212308 | GEO

SYK coordinates neuroprotective microglial responses in neurodegenerative disease [Bulk RNA-seq]

2022-10-15 | GSE212277 | GEO

SYK coordinates neuroprotective microglial responses in neurodegenerative disease

Project description:SYK coordinates neuroprotective microglial responses in neurodegenerative disease

| PRJNA874943 | ENA

SYK coordinates neuroprotective microglial responses in neurodegenerative disease [scRNA-seq]

Project description:SYK coordinates neuroprotective microglial responses in neurodegenerative disease [scRNA-seq]

| PRJNA874948 | ENA

SYK coordinates neuroprotective microglial responses in neurodegenerative disease [Bulk RNA-seq]

Project description:SYK coordinates neuroprotective microglial responses in neurodegenerative disease [Bulk RNA-seq]

| PRJNA874744 | ENA

Myc activation coordinates gene transcription and protein translation responses

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Sphingobium sp. SYK-6 treated with several carbon sources

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Epigenomic analysis of Parkinson's disease neurons identifies TET2 loss as neuroprotective

Project description:This SuperSeries is composed of the SubSeries listed below.

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Multi-OMIC analysis of Huntington disease reveals a neuroprotective astrocyte state

Project description:This SuperSeries is composed of the SubSeries listed below.

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