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Maintenance of genome stability in the face of DNA damage is essential for cellular homeostasis and prevention of cancer and brain degeneration. The DNA damage response (DDR) is a complex response that is rapidly activated when a DNA lesion occurs in chromosomal DNA. Mutations affecting the proteins involved in the DDR can lead to genomic instability syndromes that involve tissue degeneration, cancer predisposition, premature aging, and brain mal-development and degeneration. Mutation of the kinase ATM leads to a prototype genomic instability syndrome, ataxia-telangiectasia (A-T). A-T is characterized by progressive cerebellar degeneration, immunodeficiency, genome instability, premature aging, gonadal dysgenesis, extreme radiosensitivity, and high incidence of lymphoreticular malignancies. One of the most devastating symptoms of A-T — cerebellar ataxia — develops progressively into general motor dysfunction. Based on our previous studies we hypothesized that the neurological deficits in genomic instability disorders stem (at least in part) from significant reduction in functionality of glial cells. We further hypothesized that impaired vascularization affects the environment in which the neurons and glial cells function, thereby reducing neuronal cell functionality. We found that ATM deficiency led to aberrant astrocytic morphology and alterations of vasculature both in cerebellum and the visual system. Moreover, we found reduced myelin basic protein immunoreactivity and signs of inflammation in ATM-deficient cerebella and optic nerve.  Interestingly, similar findings have been reported in patients with other genomic instability disorders. These observations bolster the notion that astrocyte-specific pathologies and hampered vascularization and astrocyte-neuron interactions in the CNS play crucial roles in the etiology of genome instability brain disorders and underlie brain degeneration at specific sites.

Thyroid hormones (THs) are essential for the development and function of the central nervous system (CNS), not only for neuronal cells but also for glial development and differentiation. In adult CNS, both hypo- and hyper-thyroidism may affect psychological condition and potentially increase the risk of cognitive impairment and neurodegeneration including Alzheimer’s disease (AD). We have reported non-genomic effects of tri-iodothyronine (T3) on microglial functions and its signaling in vitro (MORI et al., 2015). Here we report the effects of hyperthyroidism on glial cells in vivo using young and old male and female mice. Immunohistochemical analyses showed glial activation are sex- and age-dependent. We also injected fluorescent-labeled amyloid β peptide (Aβ1-42) intracranially to L-thyroxine (T4)–injected hyperthyroid model mice and observed sex-dependent microglial phagocytosis in vivo as well. These results may partly explain the gender- and age-dependent differences in neurological and psychological symptoms of thyroid dysfunction.

Classically, the central nervous system (CNS) was considered to contain neurons and three main types of glial cells - astrocytes, oligodendrocytes, and microglia.  Now, it has been clearly established that NG2-glia are a fourth glial cell type that are defined by their expression of the NG2 chondroitin sulfate proteoglycan (Cspg4).  NG2-glia are also known as oligodendrocyte precursor cells (OPCs) and express the alpha receptor for platelet-derived growth factor (Pdgfra) as well as other oligodendrocyte lineage markers. NG2-glia are most numerous during CNS development when they are responsible for massive generation of oligodendrocytes, the myelin-forming cells of the CNS. A significant population of NG2-glia persist in the adult CNS, where they generate oligodendrocytes throughout life. A unique feature of NG2-glia is that they receive synaptic inputs from neurons and are able to respond rapidly to neurotransmission via their specific ion channel and receptor profiles. Moreover, synaptic and neuronal integrity depend on NG2-glia. Notably, concomitant disruption of NG2-glia, myelin and neurotransmission are key features of many neuropathologies, including Multiple Sclerosis and Alzheimer’s disease (AD). The fact that neurotransmission both regulates and is reliant on NG2-glia and myelin raises the ‘chicken and egg’ question of what comes first – disruption of NG2-glia/myelin or synapses/neurons. It is more useful to think of neurons, NG2-glia and oligodendrocytes/myelin as being functionally integrated and interdependent units, whereby disruption of any one can result in a vicious cycle with potentially devastating effects on CNS function.

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