Keywords
Telomere shortening
Cellular senescence
α-Synuclein aggregation
GBA gene
TERT
How to Cite
Abstract
Parkinson’s disease (PD), a progressive neurodegenerative disorder, is increasingly recognized as a disorder of accelerated cellular aging, driven by telomere shortening, cellular senescence, mitochondrial dysfunction, and chronic neuroinflammation. Central to its pathophysiology is the accumulation of α-synuclein aggregates, which trigger astrocyte and microglial senescence, leading to the secretion of pro-inflammatory SASP factors and creating a toxic neural microenvironment. These processes are tightly interwoven with mitochondrial impairment and the generation of reactive oxygen species (ROS), which accelerate telomere attrition and perpetuate neuronal loss through a self-reinforcing feedback loop. Dysregulation of key molecular regulators such as telomerase reverse transcriptase (TERT), GBA mutations, and the SATB1-miR22 axis further exacerbate lysosomal dysfunction, senescence, and α-synuclein accumulation. TERT, though neuroprotective when upregulated, is often downregulated in PD, while GBA mutations impair autophagy and contribute to a senescence-like phenotype in dopaminergic neurons. The SATB1-miR22-GBA network links epigenetic regulation to lysosomal failure and cellular aging. These interconnected mechanisms illuminate a multifactorial model of PD pathogenesis where senescence and telomere instability serve as central hubs. Therapeutic strategies targeting telomerase activation, clearance of senescent cells via senolytics, and modulation of the GBA/SATB1-miR22 pathway represent promising avenues for mitigating neurodegeneration and improving clinical outcomes in aging-related neurodegenerative diseases such as PD.v
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