Parkinson’s disease (PD) is the most common brain motor disorder, characterized by a substantial loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Motor impairments, such as dyskinesia, bradykinesia, and resting tremors, are the hallmarks of PD. Despite ongoing research, the exact PD pathogenesis remains elusive due to the disease intricacy and difficulty in conducting human studies. Zebrafish (Danio rerio) has emerged as an ideal model for researching PD pathophysiology. Even though 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used to induce PD in zebrafish, behavioural findings are frequently limited to a single time point (24 hours post-injection). In this sense, we aim to demonstrate the effects of MPTP on zebrafish swimming behaviour at multiple time points. We administered a single dosage of MPTP (200μg/g bw) via intraperitoneal injection (i/p) and assessed the locomotor activity and swimming pattern at 0h, 24h, and 96h post-injection through an open field test. Analysis of the behaviour revealed significant reductions in swimming velocity (cm/s) and distance travelled (cm), concurrent with an increase in freezing maintenance (duration and bouts) in zebrafish injected with MPTP. In addition, the MPTP-injected zebrafish exhibited complex swimming patterns, as measured by the turn angle, meander, and angular velocity, and showed abnormal swimming phenotypes, including freezing, looping, and erratic movement. To conclude, MPTP administration into adult zebrafish induced hypolocomotion and elicited motor incoordination. Plus, the effects of MPTP were observable 24 hours after the injection and still detectable 96 hours later. These findings contribute to the understanding of MPTP effects on adult zebrafish, particularly in terms of swimming behaviours, and may pave the way for a better understanding of the establishment of PD animal models in the future.

Parkinson's disease (PD) is the most prevalent brain motor disorder and is frequently regarded as an idiopathic and sporadic disease due to its unclear etiology. Although the pathological mechanisms of PD have already been investigated at various omics levels, no disease-modifying drugs are currently available. At the moment, treatments can only provide symptomatic relief to control or improve motor symptoms. Parkinson's disease is a multifactorial disease, the development and progression of which are influenced by multiple factors, including the genetic markups and the environment. As an indispensable component of our daily life, nutrition is considered one of the most robust environmental factors affecting our health. Consequently, depending on our dietary habits, nutrition can either induce or reduce our susceptibility to PD. Epigenetic mechanisms regulate gene expression through DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) activity. Accumulating evidence from nutriepigenomics studies has reported altered epigenetic mechanisms in clinical and pre-clinical PD models, and the potential role of nutrition in modifying the changes. In addition, through nutrigenetics and nutrigenomics studies, the diet-gene, and gene-diet interactions concerning PD development and progression have been investigated. Herein, current findings on the roles of nutrition in epigenetic mechanisms underpinning PD development and progression are discussed. Recent advancements in the multi-omics approach in PD nutrition research are also underlined. The ability of nutrients to influence epigenetic mechanisms and the availability of multi-omics applications compel the immediate use of personalized nutrition as adjuvant therapy for PD.

High-mobility group box 1 (HMGB1) has been implicated as a key player in two critical factors of Parkinson’s disease (PD): mitochondrial dysfunction and neuroinflammation. However, the specific role of HMGB1 in PD remains elusive. We investigated the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration on mitochondrial dysfunction and HMGB1-associated inflammatory genes as well as locomotor activity in zebrafish, aiming to elucidate the role of HMGB1 in PD. Adult zebrafish received MPTP injections, and locomotor activity was measured at 24- and 48-h post-administration. Gene expression levels related to mitophagy (fis1, pink1, and park2) and HMGB1-mediated inflammation (hmgb1, tlr4, and nfkb) were quantified through RT-qPCR analysis. Following MPTP injection, the significant increase in transcript levels of fis1, pink1, and park2 indicated notable changes in PINK1/Parkin mitophagy, while the upregulation of hmgb1, tlr4, and nfkb genes pointed to the activation of the HMGB1/TLR4/NFκB inflammatory pathway. Furthermore, MPTP-injected zebrafish exhibited decreased locomotor activity, evident through reduced distance travelled, mean speed, and increased freezing durations. HMGB1 plays a major role in cellular processes as it is involved in both the mitophagy process and functions as a pro-inflammatory protein. MPTP administration in adult zebrafish activated mitophagy and inflammatory signaling, highlighting the significant role of HMGB1 as a mediator in both processes and further emphasizing its significant contribution to PD pathogenesis.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism via its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP ⁺ ), which structurally mimics dopamine and enters dopaminergic neurons via the dopamine transporter (DAT). To visually depict this mimicry, we performed ligand-protein docking analysis on two species: humans and zebrafish. Human DAT (PDB ID: Q01959) and zebrafish DAT (UniProt ID: Q90ZV1) proteins were prepared with AutoDock Tools. Meanwhile, MPP+ (PubChem ID: CID_39484) and dopamine (PubChem ID: CID_681) ligands were prepared and optimized using the General AMBER Force Field (GAFF) tool. Docking with AutoDock Vina used identical grid parameters of 40 x 40 x 40 Å, which allows blind docking. Binding affinities and interactions were analyzed and visualized using PyMol and LigPlot+. MPP+ exhibited comparable binding affinities to dopamine in both species (human: -7.2 vs -6.1 kcal/mol; zebrafish: -7.6 vs -6.4 kcal/mol), sharing seven out of nine binding residues in humans and nine out of twelve in zebrafish. Spatial overlap with dopamine binding site suggests MPP+ exploits DAT for neuronal entry. However, static docking limitations warrant dynamic validation. This study provides computational evidence for the dopamine-mimetic mechanism of MPP+ but underscores the need for molecular dynamics (MD) simulation and experimental confirmation.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting more than 8.5–10 million people worldwide. Despite decades of research, no disease-modifying therapy is currently available, and existing treatments primarily provide symptomatic relief. Therapeutic development is further hindered by the multifactorial nature of PD and the late emergence of clinical symptoms, which typically occur after substantial dopaminergic neuronal loss. A comprehensive understanding of the interconnected molecular networks underlying disease progression is therefore essential for identifying effective therapeutic strategies. Recent advances in multi-omics technologies have expanded our understanding of the genetic, molecular, and metabolic alterations associated with PD, however, integrating these diverse datasets to distinguish conserved pathogenic mechanisms from model- or context-specific responses remains challenging. Cross-species integration of multi-omics datasets from complementary non-mammalian models, particularly the fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio), provides a systems-level approach for identifying conserved disease-associated networks. Comparative analyses reveal convergent molecular alterations across multiple interconnected pathological processes, highlighting the potential of these models to uncover conserved mechanisms of PD pathogenesis. Integration of these molecular networks through multimodal and computational approaches may further facilitate therapeutic target prioritization and establish a stepwise translational pipeline from high-throughput discovery in flies and zebrafish to validation in mammalian models and human studies. This review examines multi-omics findings from flies and zebrafish across four key pathophysiological processes in PD, including proteostasis disruption, mitochondrial dysfunction, oxidative stress, and neuroinflammation, and evaluates their potential for identifying conserved disease mechanisms and therapeutic targets.