Role of carboxyl-terminal modulator protein in autophagy and senescence of human induced pluripotent stem cells

University Of Virginia, Charlottesville VA

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Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Aging is the most significant risk factor for AD. It is known that brain aging is with decreased autophagy, a biological process to clean damaged organelles and misfolded proteins. We have shown that carboxyl-terminal modulator protein (CTMP) is increased in the brain with aging in rats. Our ongoing study supported by the parent grant has shown that CTMP increase contributes to the decreased autophagy in the brain of rats. Our preliminary data showed that there was an increase in CTMP mRNA levels in the brain of old people. It is possible that our findings in rats may be applicable in humans. Since decreased autophagy may contribute to cell senescence, CTMP may regulate cell senescence. However, the role of CTMP in cell senescence is not known in rodents and humans. Thus, we hypothesize that CTMP reduces autophagy and induces senescence in the human induced pluripotent stem cells (iPSC) with or without AD pathology. We will test this hypothesize in this supplement request project. iPSC is used because it is not possible to test our hypothesis in humans under in vivo conditions and iPSC holds a great potential in cell therapy for various diseases. iPSC generated from healthy individual or from a patient with an AD mutation will be infected with lentivirus to overexpress CTMP or silence CTMP expression. These cells will be subject to the evaluation of autophagy and cell senescence. These studies may identify a molecular target for improving the health of iPSC and advance our knowledge on the molecular process of cell senescence in the presence or absence of AD pathology, an aging-dependent neuropathology.