Association of p53 with Neurodegeneration in Parkinson’s Disease

Abstract

p53 is a vital transcriptional protein implicated in regulating diverse cellular processes, including cell cycle arrest, DNA repair, mitochondrial metabolism, redox homeostasis, autophagy, senescence, and apoptosis. Recent studies have revealed that p53 levels and activity are substantially increased in affected neurons in cellular and animal models of Parkinson’s disease (PD) as well as in the brains of PD patients. p53 activation in response to neurodegenerative stress is closely associated with the degeneration of dopaminergic neurons accompanied by mitochondrial dysfunction, reactive oxygen species (ROS) production, abnormal protein aggregation, and impairment of autophagy, and these pathogenic events have been implicated in the pathogenesis of PD. Pathogenic p53 integrates diverse cellular stresses and activate these downstream events to induce the degeneration of dopaminergic neurons; thus, it plays a crucial role in the pathogenesis of PD and appears to be a potential target for the treatment of the disease. We reviewed the current knowledge concerning p53-dependent neurodegeneration to better understand the underlying mechanisms and provide possible strategies for PD treatment by targeting p53.

Proteomic Analysis of Protective Effects of Dl-3-n-Butylphthalide against mpp + -Induced Toxicity via downregulating P53 pathway in N2A Cells

“…It was well known that p53 was essential for inducing apoptosis and was responsible for diverse cellular stresses. Pathogenic p53 integrated the cellular stresses comprising the generation ROS, inflammation, abnormal protein accumulation and Ca 2+ overloading, to trigger cell death [42][43][44]. Recent study demonstrated that the specific deletion of p53 gene could eliminate dopaminergic neuronal cell death and further decrease motor deficits in MPTP-treated mice [45].…”

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

“…For example, upregulation of DNA damage and p53, a powerful pro-apoptotic factor, has been reported in a MPTP-induced mouse model, and p53 inhibition can prevent neurodegeneration and ameliorate motor deficits [ 148 , 149 ]. Similarly, DNA damage and apoptotic phenotypes have been observed in other PD toxin models, as well as transgenic mouse models of PD, although p53 may not always be the mediator of cell death in these paradigms [ 29 , 147 , 150 , 151 , 152 ].…”

“…These factors then facilitate the execution of apoptosis in a caspase-dependent or caspase-independent manner [ 144 , 145 ]. In the context of PD, there is abundant evidence from both patients and experimental models supporting the role of DNA damage-triggered intrinsic apoptotic pathways in DA neurodegeneration [ 146 , 147 ]. For example, upregulation of DNA damage and p53, a powerful pro-apoptotic factor, has been reported in a MPTP-induced mouse model, and p53 inhibition can prevent neurodegeneration and ameliorate motor deficits [ 148 , 149 ].…”

Emerging roles of interferon-stimulated gene-15 in age-related telomere attrition, the DNA damage response, and cardiovascular disease

“…This complexity might be related to the cross-regulation between ISG15 and key tumor suppressors. One of the few identified and validated ISG15 substrates is the tumor suppressor p53, a pivotal transcription factor that coordinates the expression of many DDR effector genes that induce cell-cycle arrest, DNA repair, autophagy, senescence, and apoptosis ( Sandy et al, 2020 ; Luo et al, 2022 ). ISG15 and p53 modulate each other at several levels.…”