Nuclear alpha-synuclein accelerates cell senescence and neurodegeneration.

BACKGROUND: The progression of Parkinson's disease (PD) is related to ageing. The accumulation of nuclear alpha-synuclein (α-syn) may accelerate the occurrence of neurodegenerative diseases, but its role in PD remains poorly understood. METHODS: In the present study, α-syn expression was specifically targeted to the nucleus by constructing an adeno-associated virus (AAV) vector in which a nuclear localization sequence (NLS) was added to the α-syn coding sequence. Virus-mediated gene transfer, behavioural tests, RNA-Seq, immunohistochemistry, western blotting, and quantitative real-time PCR were then performed. RESULTS: In vivo experiments using a mouse model showed that nuclear α-syn increased the severity of the PD-like phenotype, including the loss of dopaminergic neurons concomitant with motor impairment and the formation of α-syn inclusions. These nuclear inclusions contained α-syn species of high molecular weights and induced strong transcriptional dysregulation, especially induced high expression of p21 and senescence-associated secretory phenotype (SASP)-related genes. In addition, the transcriptional alterations induced by nuclear α-syn were associated with gliosis, inflammation, oxidative and DNA damage, and lysosomal dysfunction, and they eventually accelerated neuronal loss and neurodegeneration. CONCLUSIONS: Our results suggest that nuclear α-syn plays a crucial role in PD pathogenesis.

Nuclear localization of alpha-synuclein induces anxiety-like behavior in mice by decreasing hippocampal neurogenesis and pathologically affecting amygdala circuits.

Fear and anxiety are common in Parkinson's disease (PD) and may be caused by pathologies outside the dopaminergic system. Increasing evidence has shown that alpha-synuclein (α-syn) is involved in the development of anxiety in PD. In this study, we examined the effects of α-syn nuclear translocation on anxiety-like behavior in mice by overexpressing α-syn in the nuclei of the cell in the hippocampus. Our results show that α-syn overexpression in the nuclei increased the excitability of hippocampal neurons and activated NG2 glial cells and promoted the synthesis and release of γ-aminobutyric acid (GABA). And nuclear localization of α-syn led to the loss of neurotrophic factors and decreased neurogenesis. Meanwhile, the hippocampus and amygdala acted synergistically, resulting in pathologic accumulation of α-syn and gliosis in the amygdala and caused loss of interneurons. These events led to the impairments of hippocampus and amygdala function, which ultimately induced anxiety-like behavior in mice. The findings obtained in our present study indicate that excessive nuclear translocation of α-syn in hippocampal neurons and damage to the amygdala circuits may be important in the development of anxiety in PD.

pNaktide mitigates inflammation-induced neuronal damage and behavioral deficits through the oxidative stress pathway.

Neuroinflammation is closely related to the etiology and progression of neurodegenerative diseases such as Parkinson disease and Alzheimer disease. pNaktide, an Src inhibitor, exerts antioxidant effects by mimicking Na/K-ATPase. It has been verified that its anti-inflammation and anti-oxidation ability could be embodied in obesity, steatohepatitis, uremic cardiomyopathy, aging, and prostate cancer. This study aimed to investigate the effects and mechanisms of pNaktide in lipopolysaccharide (LPS)-induced behavioral damage, neuroinflammation, and neuronal damage. We found that pNaktide improved anxiety, memory, and motor deficits. pNaktide inhibited MAPK and NF-κB pathways induced by TLR4 activation, inhibited the NLRP3 inflammasome complex, and reduced the expression of inflammatory factors, complement factors, and chemokines. pNaktide inhibited the activation of Nrf2 and HO-1 antioxidant stress pathways by LPS and reduced the level of oxidative stress. Inhibition of autophagy and enhancement of apoptosis induced by LPS were also alleviated by pNaktide, which restored LPS-induced injury to newborn neurons in the hippocampus region. In summary, pNaktide attenuates neuroinflammation, reduces the level of oxidative stress, has neuroprotective effects, and may be used for the treatment of neuroinflammation-related diseases.

Nuclear localization of alpha-synuclein affects the cognitive and motor behavior of mice by inducing DNA damage and abnormal cell cycle of hippocampal neurons.

Nuclear accumulation of alpha-synuclein (α-syn) in neurons can promote neurotoxicity, which is considered the key factor in the pathogenesis of synucleinopathy. The damage to hippocampus neurons driven by α-syn pathology is also the potential cause of memory impairment in Parkinson's disease (PD) patients. In this study, we examined the role of α-syn nuclear translocation in the cognition and motor ability of mice by overexpressing α-syn in cell nuclei in the hippocampus. The results showed that the overexpression of α-syn in nuclei was able to cause significant pathological accumulation of α-syn in the hippocampus, and quickly lead to memory and motor impairments in mice. It might be that nuclear overexpression of α-syn may cause DNA damage of hippocampal neurons, thereby leading to activation and abnormal blocking of cell cycle, and further inducing apoptosis of hippocampal neurons and inflammatory reaction. Meanwhile, the inflammatory reaction further aggravated DNA damage and formed a vicious circle. Therefore, the excessive nuclear translocation of α-syn in hippocampal neurons may be one of the main reasons for cognitive decline in mice.