Comprehensive Analysis and Experimental Validation of the Parkinson's Disease Lysosomal Gene ACP2 and Pan-cancer.

The pivotal role of lysosomal function in preserving neuronal homeostasis is recognized, with its dysfunction being implicated in neurodegenerative processes, notably in Parkinson's disease (PD). Yet, the molecular underpinnings of lysosome-related genes (LRGs) in the context of PD remain partially elucidated. We collected RNA-seq data from the brain substantia nigra of 30 PD patients and 20 normal subjects from the GEO database. We obtained molecular classification clusters from the screened lysosomal expression patterns. The lysosome-related diagnostic model of Parkinson's disease was constructed by XGBoost and Random Forest. And we validated the expression patterns of signature LRGs in the diagnostic model by constructing a PD rat model. Finally, the linkage between PD and cancer through signature genes was explored. The expression patterns of the 33 LRGs screened can be divided into two groups of PD samples, enabling exploration of the variance in biological processes and immune elements. Cluster A had a higher disease severity. Subsequently, critical genes were sieved through the application of machine learning methodologies culminating in the identification of two intersecting feature genes (ACP2 and LRP2). A PD risk prediction model was constructed grounded on these signature genes. The model's validity was assessed through nomogram evaluation, which demonstrated robust confidence validity. Then we analyzed the correlation analysis, immune in-filtration, biological function, and rat expression validation of the two genes with common pathogenic genes in Parkinson's disease, indicating that these two genes play an important role in the pathogenesis of PD. We then selected ACP2, which had a significant immune infiltration correlation, as the entry gene for the pan-cancer analysis. The pan-cancer analysis revealed that ACP2 has profound associations with prognostic indicators, immune infiltration, and tumor-related regulatory processes across various neoplasms, suggesting its potential as a therapeutic target in a range of human diseases, including PD and cancers. Our study comprehensively analyzed the molecular grouping of LRGs expression patterns in Parkinson's disease, and the disease progression was more severe in cluster A. And the PD diagnosis model related to LRGs is constructed. Finally, ACP2 is a potential target for the relationship between Parkinson's disease and tumor.

Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.

Parkinson's disease (PD) is characterized by the severe loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor dysfunction. The onset of PD is often accompanied by neuroinflammation and α-Synuclein aggregation, and extensive research has focused on the activation of microglial NLRP3 inflammasomes in PD, which promotes the death of dopaminergic neurons. In this study, a model of cerebral inflammatory response was constructed in wild-type and Parkin＋/－ mice through bilateral intraventricular injection of LPS. LPS-induced activation of the NLRP3 inflammasome in wild-type mice promotes the progression of PD. The use of MCC950 in wild mice injected with LPS induces activation of Parkin/PINK and improves autophagy, which in turn improves mitochondrial turnover. It also inhibits LPS-induced inflammatory responses, improves motor function, protects dopaminergic neurons, and inhibits microglia activation. Furthermore, Parkin＋/－ mice exhibited motor dysfunction, loss of dopaminergic neurons, activation of the NLRP3 inflammasome, and α-Synuclein aggregation beginning at an early age. Parkin ± mice exhibited more pronounced microglia activation, greater NLRP3 inflammasome activation, more severe autophagy dysfunction, and more pronounced motor dysfunction after LPS injection compared to wild-type mice. Notably, the use of MCC950 in Parkin ± mice did not ameliorate NLRP3 inflammasome activation, autophagy dysfunction, or α-synuclein aggregation. Thus, MCC950 can only exert its effects in the presence of Parkin/PINK1, and targeting Parkin-mediated NLRP3 inflammasome activation is expected to be a potential therapeutic strategy for Parkinson's disease.

Ubiquitin ligase RFWD2 promotes dendritic spine and synapse formation by activating the ERK/PEA3/c-Jun pathway in rat cerebral cortical neurons.

The regulation of protein degradation through the ubiquitin-proteasome system is essential for normal brain development, axon growth, synaptic growth and plasticity. The E3 ubiquitin ligase RFWD2 plays a key role in the onset and development of neurological diseases, including the pathogenesis of Alzheimer's disease (AD), but the mechanisms controlling the homeostasis of neuronal synaptic proteins are still poorly understood. Here, we showed that the expression level of RFWD2 gradually decreased with the age of the rats and was negatively correlated with the development of cerebral cortical neurons and dendrites in vivo. RFWD2 was shown to localize to presynaptic terminals and some postsynaptic sides of both excitatory synapses and inhibitory synapses via colocalization with neuronal synaptic proteins (SYN, PSD95, Vglut1 and GAD67). Overexpression of RFWD2 promoted dendrite development and dendritic spine formation and markedly decreased the expression of synaptophysin and PSD95 by reducing the expression of ETV1, ETV4, ETV5 and c-JUN in vitro. Furthermore, the whole-cell membrane slice clamp results showed that RFWD2 overexpression resulted in greater membrane capacitance in neuronal cells, inadequate cell repolarization, and a longer time course for neurons to emit action potentials with decreased excitability. RFWD2 regulates dendritic development and plasticity, dendritic spine formation and synaptic function in rat cerebral cortex neurons by activating the ERK/PEA3/c-Jun pathway via a posttranslational regulatory mechanism and can be used as an efficient treatment target for neurological diseases.

The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.