Senescence and impaired DNA damage responses in alpha-synucleinopathy models

Abstract

Abstractα-Synuclein is a crucial element in the pathogenesis of Parkinson’s disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence. Transcriptome analysis showed that α-synuclein overexpression led to cellular senescence with activation of the p53 pathway and DNA damage responses (DDRs). Chromatin immunoprecipitation analyses using p53 and γH2AX, chromosomal markers of DNA damage, revealed that these proteins bind to promoters and regulate the expression of DDR and cellular senescence genes. Cellular marker analyses confirmed cellular senescence and the accumulation of DNA double-strand breaks. The non-homologous end joining (NHEJ) DNA repair pathway was activated in α-synuclein-overexpressing cells. However, the expression of MRE11, a key component of the DSB repair system, was reduced, suggesting that the repair pathway induction was incomplete. Neuropathological examination of α-synuclein transgenic mice showed increased levels of phospho-α-synuclein and DNA double-strand breaks, as well as markers of cellular senescence, at an early, presymptomatic stage. These results suggest that the accumulation of DNA double-strand breaks (DSBs) and cellular senescence are intermediaries of α-synuclein-induced pathogenesis in PD.

Age-Related Midbrain Inflammation and Senescence in Parkinson’s Disease

“…Mutations in PINK1 and PARKIN, which are involved in mitochondrial turnover, are causative for PD (Kitada et al, 1998;Valente et al, 2004) and mitochondrial impairment triggers senescence. Additionally, α-synuclein, a hallmark protein aggregate seen in PD, induces DNA damage and cellular senescence (Yoon et al, 2022). In line with this, lysosomal dysfunction is central to PD pathology (Wallings et al, 2019) and can trigger cellular senescence (Tai et al, 2017).…”

“…Cellular senescence can be described as a multistep evolution, with an initial transition into stable cell-cycle arrest characterized by prolonged p21 and/or p16 activity. Activation of p16 or p21 is usually driven by activation of the DNA damage response machinery (Yoon et al, 2022). Progression into a full state of senescence includes lamin B1 downregulation, triggering both local and global modifications in chromatin methylation (Hayflick and Moorhead, 1961;Kurz et al, 2000;Beauséjour et al, 2003;Shimi et al, 2011;van Deursen, 2014).…”

Physical Activity Rewires the Human Brain against Neurodegeneration

“…Increased DNA double-strand breaks and altered levels of DNA repair proteins have been reported in the hippocampus of AD subjects [ 22 ] and neuronal and glial cells in the early stages of the disease [ 23 ]. Likewise, DNA strand breaks and damage response pathways may contribute to disease pathology in PD [ 24 , 25 ]. These findings suggest that high physical activity influences the transcriptional regulation of genes involved in DNA damage, possibly preventing neurodegeneration.…”

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

“…Sequential treatment with RA and BDNF induces a neuronal morphology with axonal elongation and increased expression of NeuN and tyrosine hydroxylase [ 123 ]. Several RNA-seq datasets of SH-SY5Y cells combining RA-induced differentiation and αS overexpression are publicly available [ 124 , 125 , 126 ] ( Table 1 ). αS binds RA and translocates to the nucleus, where it regulates gene transcription via RA-associated nuclear receptors [ 124 ].…”