SNCA-targeted transcriptional repression therapy alleviates pathological and behavioral perturbations in a Parkinson's disease mouse model

CRISPR/Cas9-mediated knockout of NEAT1 attenuates neurotoxicity in 6-hydroxydopamine model of Parkinson’s disease

Objective(s): Parkinson’s disease (PD), a progressive neurodegenerative condition, involves the degeneration of dopaminergic neurons and the aggregation of α-synuclein (SNCA); however, the molecular mechanisms of this disorder remain incompletely understood. Materials and Methods: This study explores the role of the long non-coding RNA NEAT1 in PD by employing CRISPR/Cas9-mediated knockout in SH-SY5Y neuroblastoma cells treated with 6-hydroxydopamine (6-OHDA). Results: Deletion of NEAT1 was associated with increased cellular viability, attenuated both cytotoxicity and apoptosis, and elevated total antioxidant capacity (TAC), alongside a marked down-regulation of SNCA expression. Mechanistically, NEAT1 knockout was accompanied by increased hsa-let-7a-5p and decreased miR-506-3p expression, suggesting its function as a competing endogenous RNA (ceRNA) in miRNA-mediated stress pathways. Tyrosine hydroxylase (TH) levels remained unchanged, indicating that NEAT1 may influence neurotoxicity through post-transcriptional mechanisms. Conclusion: These results suggest NEAT1 is a crucial modulator of neurotoxicity in PD, with its inhibition offering therapeutic promise. Despite the in vitro nature of this study, our findings provide foundational insight into NEAT1’s dualistic roles in neurodegeneration and underscore its potential as a therapeutic target in PD.

Integrative Nutrigenomic Systems Biology Analysis of Traditional Chinese Medicine Interventions in Parkinson’s Disease: Nutrient-Gene-Disease Network Perspectives

The pathology of PD is characterized by progressive degeneration of dopaminergic neurons, although the full regulatory network involved in this process is not yet fully established. The present research employed a multi-omic systems biology design, integrating transcriptomic, functional, epigenetic, and microRNA analyses to develop a mechanistic model of neurodegeneration in the substantia nigra. We have determined six differentially expressed genes, such as tyrosine hydroxylase (TH), solute carrier family 18 member 2 (SLC18A2/VMAT2), and engrailed 1 (EN1), that are of critical interest in the disruption of the dopaminergic synapse and the inability to load vesicular neurotransmitters (fold enrichment: 2164.22). Notably, we have identified a candidate dual regulatory axis underlying the silencing of these neuroprotective genes. In this mechanism, repressive histone marks (H3K27me3 and H3K9me3) are concurrent, and post-transcriptional repression via specific microRNAs, in particular, hsa-miR-431-3p (EN1) and mmu-miR-362-5p (SLC18A2), is involved. The combined model thus finds a mutual dysregulation of epigenetics and microRNA as the main cause of gene silencing. Besides, the Traditional Chinese Medicine (TCM) components were analyzed to identify compounds that can interact with the core targets (TH and SLC18A2), thereby providing translational potential. The results identify candidate TCM compounds predicted to interact with core targets (TH and SLC18A2), providing hypothesis-generating leads for multi-target interventions that may modulate the repressive epigenetic landscape, suppress regulatory microRNAs, and engage dopaminergic pathways. Predicted interactions require experimental validation to distinguish beneficial modulation from potential inhibition. This would seek to reverse severe neuronal activity and halt the advancement of Parkinson's disease. These findings illustrate a neuro-nutrigenomic application in which dietary-derived and herbal compounds may modulate gene expression and epigenetic marks in Parkinson’s disease.

miR-584-5p suppresses Aβ1-42-induced apoptosis in Alzheimer's disease cell model via targeting of HDAC1.

Targeting of CH25H to boost p62-dependent autophagic degradation of α-synuclein in cell and mouse models of Parkinson's disease.

Insufficient understanding of α-synuclein turnover mechanisms has impeded successful clinical translation for Parkinson's disease (PD). Here, we pinpointed cholesterol 25-hydroxylase (CH25H) as a pivotal regulator of α-synuclein degradation. Through bulk RNA sequencing of substantia nigra tissue from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, along with reanalysis of published datasets from induced pluripotent stem cell-derived astrocytes of patients with PD, we observed an elevated CH25H expression in PD-associated astrocytes. This finding was validated by combined fluorescence in situ hybridization for Ch25h and immunofluorescence staining for GFAP in mouse substantia nigra sections. Conditional knockout or knockdown of astrocytic Ch25h alleviated PD-like motor deficits and reduced dopaminergic neuronal loss in MPTP and α-synuclein preformed fibril (PFF) mouse models. Using 4D label-free proteomics and molecular docking approaches, we uncovered a shared binding domain on p62 where both CH25H and α-synuclein interact. Proximity ligation assays in cultured astrocytes showed that Ch25h overexpression promoted formation of p62/CH25H complex, whereas it inhibited p62/α-synuclein interaction. Conversely, Ch25h knockdown enhanced p62/α-synuclein complex formation and facilitated α-synuclein degradation. 25-Hydroxycholesterol, the enzymatic by-product of CH25H, did not affect the expression of α-synuclein in astrocytes, suggesting an activity-independent influence of CH25H on α-synuclein clearance. In addition, treatment with a p62 polypeptide (60 to 90 amino acids) effectively facilitated α-synuclein clearance by sequestering free CH25H in both cultured astrocytes and mice in the PFF model. Collectively, our study provides insights into the mechanisms underlying α-synuclein turnover and suggests promising avenues for disease-modifying interventions in synucleinopathies.

MeCP2 Dosage Control in Rett Syndrome: Non-Coding RNA-Based and Epigenetic Strategies for Safer Gene Therapy

Clinically applicable gene therapy for RTT will likely need to move beyond simple MECP2 replacement and instead rely on precise cell- and dose-dependent regulation of its expression, with an emphasis on non-coding RNA-based and epigenetic mechanisms.

Optimized AAV to express the unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease features in mouse models