Unraveling Parkinson's disease: The mystery of mitochondria and the role of aging.

Abstract

Parkinson's disease (PD) is a complex neurodegenerative disorder that poses significant burden on patients and families. Its exact cause is unknown, resulting in limited effective treatments. Mitochondrial dysfunction, linked to genetics, aging, oxidative stress, and environmental factors, is central to PD. Healthy elderly individuals have a compensatory mitochondrial DNA (mtDNA) mechanism in brain cells, but this mechanism is impaired in PD patients, leading to mtDNA reduction, respiratory chain dysfunction, decreased adenosine triphosphate (ATP) synthesis, and inadequate neuron energy. Aging increases oxidative stress, impairing mitochondrial function. Mitochondrial dysfunction in the dopaminergic neurons of the substantia nigra causes neuronal loss and disease progression. Aging microglia also play a crucial role, with a reduced capacity to clear neurotoxic substances, especially in the substantia nigra. A decrease in triggering receptor expressed on myeloid cells 2 (TREM2) gene expression shifts microglia to a pro-inflammatory phenotype, exacerbating neuroinflammatory responses and protein deposition. Down-regulation of the C-X3-C motif chemokine ligand 1 (CX3CL1)/C-X3-C chemokine receptor 1 (CX3CR1) signaling pathway increases the expression of pro-inflammatory cytokines, accelerating neuronal loss and disease progression. Recent research has identified a new astrocyte aging regulatory mechanism involving the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, promoting astrocyte aging and exacerbating dopamine neuronal loss and motor dysfunction. Understanding PD pathogenesis, especially mitochondrial dysfunction, aging, and glial cell changes, is crucial for developing effective treatments.