2026· Iranian Journal of Basic Medical Sciences· Vol 29, pp. 915 - 926· 0 citations· 27 references
Medicine
TL;DR
The results suggest NEAT1 is a crucial modulator of neurotoxicity in PD, with its inhibition offering therapeutic promise, and foundational insight into NEAT1’s dualistic roles in neurodegeneration is provided.
Abstract
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.
In vivo proof-of-concept for SNCA-targeted transcriptional repression therapy in a PD-mouse model is provided and its further preclinical development toward investigational new drug enablement is supported.
Bernadette O'Donovan, Joseph E. Rittiner, Suraj Upadhya et al.· Neurotherapeutics· 0 citations
Introduction: Parkinson’s disease (PD) is the most prevalent movement disorder, with global prevalence increasing by 153% since 1990. It is characterized by dopaminergic neuronal loss in the substantia nigra, driven in part by mitochondrial dysfunction and neuroinflammation. High-mobility group box 1 (HMGB1), a nuclear protein that acts as a damage-associated molecular pattern (DAMP) upon extracellular release, has been implicated in both processes, yet its role in PD remains underexplored. Hence, this study aims to investigate the role of HMGB1 and the effects of its inhibition in a zebrafish model of parkinsonism.
Materials and methods: Adult zebrafish were administered a single dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) via intraperitoneal (i/p) injection, followed by two doses of glycyrrhizin, an HMGB1 inhibitor, at day 1 and day 2 post-MPTP exposure. At day 3 post-injection, locomotor activity, gene expression, tissue morphology, and blood–brain barrier (BBB) permeability were assessed.
Results: HMGB1 inhibition improved locomotor deficits, reduced gene expression of inflammatory mediators: toll-like receptor 4b duplicate a (tlr4ba), nuclear factor kappa light polypeptide gene enhancer in B-cells 1 (nfκb), tumor necrosis factor alpha (tnfα), interleukin-1β (il1β), normalized mitochondrial quality control markers: PTEN-induced kinase 1 (pink1), parkin RBR E3 ubiquitin protein ligase (prkn), fission mitochondrial 1 (fis1), and attenuated BBB disruption. However, morphological alterations in the posterior tuberculum and subpallium regions of the brain persisted. Additionally, in silico analyses showed strong molecular interactions between 1-methyl-4-phenylpyridinium (MPP+) and dopamine transporter, as well as glycyrrhizin to HMGB1 in zebrafish, supporting translational relevance.
Conclusions: These findings suggest that HMGB1 is closely associated with the intersection of neuroinflammation and mitochondrial dysfunction in MPTP-induced parkinsonism. Modulating HMGB1 pathways helps mitigate these downstream functional and molecular impairments, highlighting its potential utility as an indirect biomarker and therapeutic target. Ultimately, this study supports the translational value of the zebrafish PD model for investigating complex neurodegenerative mechanisms.
Khairiah Razali, Mohd Hamzah Mohd Nasir, Jaya Kumar et al.· Academia Neuroscience and Br...· 0 citations
Insight is provided into the mechanisms underlying α-synuclein turnover and suggests promising avenues for disease-modifying interventions in synucleinopathies.
BACKGROUND
Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of Parkinson's disease (PD), particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons.
METHODS
We employed a BAC transgenic mouse model overexpressing human LRRK2-R1441G (BAC-hR1441G) and crossed it with TH-mito-roGFP mice to enable mitochondria-targeted redox imaging specifically in DA neurons. Acute midbrain slices from 3-, 6-, and 10-month-old mice were imaged using two-photon microscopy to assess mitochondrial oxidative stress. In parallel, mitochondrial respiratory function, membrane potential flickering events, and expression of uncoupling proteins (UCP4/UCP5) were analyzed. Spatial transcriptomic profiling was performed using the GeoMx® Digital Spatial Profiler to uncover associated molecular alterations.
RESULTS
We observed a progressive increase in mitochondrial oxidative stress in SNc DA neurons of BAC-hR1441G mice at 3, 6, and 10 months of age. This was accompanied by reduced respiratory complex activity, attenuated mitochondrial membrane potential flickering, and diminished expression of UCP4 and UCP5. Spatial transcriptomic analysis revealed dysregulation of genes linked to mitochondrial uncoupling, calcium signaling, and redox regulation in BAC-hR1441G SNc DA neurons.
CONCLUSIONS
These findings reveal an age-dependent progression of mitochondrial dysfunction in BAC-hR1441G SNc DA neurons. Dysregulation of calcium channels and uncoupling proteins emerges as a key mechanism contributing to bioenergetic failure, suggesting potential therapeutic targets to mitigate PD progression.
Yuanxin Chen, Lianteng Zhi, Shiquan Cui et al.· Molecular Neurodegeneration· 1 citation
This work generates human induced pluripotent stem cell-derived midbrain dopaminergic neurons using both a 2D differentiation protocol and a recently developed 3D method based on the microencapsulation of hiPSCs in small alginate/fibronectin beads.
A. Zanon, E. Kerschbamer, D. Riekschnitz et al.· Communications Biology· 0 citations
The combined model finds a mutual dysregulation of epigenetics and microRNA as the main cause of gene silencing, illustrating a neuro-nutrigenomic application in which dietary-derived and herbal compounds may modulate gene expression and epigenetic marks in Parkinson's disease.
