Glycogenolysis-Induced Astrocytic Serping1 Expression Regulates Neuroinflammatory Effects on Hippocampal neuron.

The bacterial pathogen, lipopolysaccharide (LPS), elicits microglial response and induces cytokine secretion that subsequently activates astrocytes. Recent findings have indicated that LPS-induced activation of postnatal glial cells has led to alterations in synapse formation in hippocampal and cortical neurons, thereby resulting in a prolonged increased risk for seizure or depression. Nevertheless, its mechanisms remain to be fully elucidated. Cellular metabolism has recently gained recognition as a critical regulatory mechanism for the activation of peripheral immune cells, as it supplies the requisite energy and metabolite for their activation. In the present study, we report that LPS did not change the expression of reported astrocyte-derived synaptogenic genes in the postnatal hippocampus; however, it induced upregulation of astrocytic complement component regulator Serping1 within the postnatal hippocampus. As a regulatory mechanism, activation of glycogen degradation (glycogenolysis) governs the expression of a subset of inflammatory-responsive genes including Serping1 through reactive oxygen species (ROS)-NF-κB axis. Our study further demonstrated that glycogenolysis is implicated in neurotoxic phenotypes of astrocytes, such as impaired neuronal synaptogenesis or cellular toxicity. These findings suggested that activation of glycogenolysis in postnatal astrocytes is an essential metabolic pathway for inducing responses in inflammatory astrocytes.

SQSTM1, a protective factor of SOD1-linked motor neuron disease, regulates the accumulation and distribution of ubiquitinated protein aggregates in neuron.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Recent studies have shown that mutations in SQSTM1 are linked to ALS. It has also been demonstrated that a systemic loss of SQSTM1 exacerbates disease phenotypes in an ALS mouse model. However, it is still unclear whether and how SQSTM1 in the central nervous system (CNS) specifically regulates ALS-associated disease phenotypes. To address this issue, we generated CNS-specific Sqstm1 deficient SOD1H46R transgenic mice, and conducted gross phenotype analyses as well as the immunohistochemical and biochemical examinations of spinal cord tissues using these mice. CNS-specific SQSTM1 deficiency accelerated the disease onset and shortened the lifespan of SOD1H46R mice. The CNS-specific SQSTM1 ablation also resulted in increased number of ubiquitin-positive aggregates, while their size rather became much smaller. Remarkably, ubiquitin-positive aggregates, which were usually present in extracellular space and/or neuropil in SOD1H46R mice, were preferentially localized to soma and neurites of spinal neurons in CNS-specific SQSTM1 deficient SOD1H46R mice. Next, to further clarify the function of SQSTM1 in neurons, we investigated the contribution of SQSTM1 to the accumulation of polyubiquitinated proteins in relation to the ubiquitin proteasome system (UPS) and the autophagy-endolysosomal system (APELS) in primary cultured motor neurons (PMNs). Loss of SQSTM1 in PMNs resulted in decreased accumulation of insoluble polyubiquitinated proteins, which was induced by simultaneous treatment with proteasome and lysosome inhibitors, suggesting a pivotal role of SQSTM1 in the formation of insoluble protein aggregates. However, SQSTM1 silencing had a limited impact on the susceptibility to proteasome and/or lysosome inhibitor-induced apoptosis in PMNs. Taken together, neuronal SQSTM1, whose functions are associated with both the UPS and APELS, might primarily regulate the distribution and accumulation of misfolded protein aggregates in the CNS, thereby protecting neurons from degeneration in mice.