: An inverse correlation between the incidence of cancer and neurodegenerative disease has been observed, with the prevalence of cancer peaking around 60 years of age, then slowly tapering off as neurodegenerative diseases increase in the elderly. Although the diseases rarely occur concurrently, the same genes are differentially expressed between the diseases, with four transcription factors found to be in common for their expression. In the brain, mature astrocytes are the origin of astrocytoma, which make up 58.2% of malignant brain tumors in patients 65 or older, while GFAP+ astrocyte-like neural stem cells from the subventricular zone give rise to glioblastoma and anaplastic astrocytoma, which make up 41.6%. Likewise, in neurodegenerative disease, a decrease in astrocyte density is observed in early disease states, and senescent astrocytes increase. Because astrocytes coordinate synaptic function, astrocyte dysfunction likely contributes to or causes initial synapse loss and cognitive decline seen in neurodegenerative disease. In non-disease states, astrocytes retain their ability to successfully re-enter the cell cycle through adult astrogenesis to maintain the neuroenvironment, and controlled astrocytic proliferation could be an important contributor to neurological function. Disruption to this astrogenic balance could account for the inverse correlation of cell cycle dysregulation resulting in malignant astrocytes and tumorigenesis, and astrocytic senescence and cell death without self-renewal in aging resulting in neurodegenerative disease. The current understanding of the astrocytic roles of the transcription factors that could be the cause of this imbalance will be discussed, as well as possible therapeutic approaches to modulate their expression in the astrocyte.
Elevated levels of γ-synuclein (γ-syn) expression have been noted in the progression of glioblastomas, and also in the cerebrospinal fluid of patients diagnosed with neurodegenerative diseases. γ-Syn can be either internalized from the extracellular milieu or expressed endogenously by human cortical astrocytes. Internalized γ-syn results in increased cellular proliferation, brain derived neurotrophic factor release and astroprotection. However, the function of endogenous γ-syn in primary astrocytes, and the relationship to these two opposing disease states are unknown. γ-Syn is expressed by astrocytes in the human cortex, and to gain a better understanding of the role of endogenous γ-syn, primary human cortical astrocytes were treated with chimera RNA interference (RNAi) targeting γ-syn after release from cell synchronization. Quantitative polymerase chain reaction analysis demonstrated an increase in endogenous γ-syn expression 48 hours after release from cell synchronization, while RNAi reduced γ-syn expression to control levels. Immunocytochemistry of Ki67 and 5-bromodeoxyuridine showed chimera RNAi γ-syn knockdown reduced cellular proliferation at 24 and 48 hours after release from cell synchronization. To further investigate the consequence of γ-syn knockdown on the astrocytic cell cycle, phosphorylated histone H3 pSer10 (pHH3) and phosphorylated cyclin dependent kinase-2 pTyr15 (pCDK2) levels were observed via western blot analysis. The results revealed an elevated expression of pHH3, but not pCDK2, indicating γ-syn knockdown leads to disruption of the cell cycle and chromosomal compaction after 48 hours. Subsequently, flow cytometry with propidium iodide determined that increases in apoptosis coincided with γ-syn knockdown. Therefore, γ-syn exerts its effect to allow normal astrocytic progression through the cell cycle, as evidenced by decreased proliferation marker expression, increased pHH3, and mitotic catastrophe after knockdown. In this study, we demonstrated that the knockdown of γ-syn within primary human cortical astrocytes using chimera RNAi leads to cell cycle disruption and apoptosis, indicating an essential role for γ-syn in regulating normal cell division in astrocytes. Therefore, disruption to γ-syn function would influence astrocytic proliferation, and could be an important contributor to neurological diseases.
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