Nörodejenerasyon ve Yaşlılık: Hücresel Yaklaşımlar
Synopsis
This review article comprehensively examines the cellular and molecular mechanisms between the aging process and neurodegenerative diseases. Aging is characterized by hallmark biological features such as genomic instability, telomere shortening, loss of proteostasis, altered intercellular communication, and mitochondrial dysfunction, serving as the major risk factor for the development of chronic neurodegenerative disorders including Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis. During cellular senescence, persistent activation of DNA damage response (DDR) mechanisms via p53 and p21 cyclin-dependent kinase inhibitors leads to irreversible growth arrest, while the secretion of SASP components triggers neuroinflammation and tissue damage. Although terminally differentiated mature neurons normally remain quiescent in the G0 phase, under pathological conditions, aberrant induction of cyclins and CDKs causes them to re-enter the cell cycle uncontrollably, ultimately leading to apoptotic cell death due to this uncompleted, abortive cycle. The disruption of cellular redox balance and the excessive accumulation of reactive oxygen species (ROS) result in severe oxidative stress, mitochondrial DNA mutations, reduced ATP production, and particularly synaptic mitochondrial damage, laying the groundwork for synaptic loss and cognitive decline. Finally, SUMOylation, a post-translational modification mechanism, plays critical roles in regulating nuclear single-strand DNA repair (TDP1) and mitochondrial fission-fusion dynamics (DRP1), directly modulating cellular responses under varying oxidative stress conditions and the toxicity of pathogenic proteins.
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