It is demonstrated that curcumin exerted neuroprotective effects in a PD model by attenuating α-syn pathology and identifying UBC9-mediated SUMOylation as a potential target for curcumin and highlighting a promising strategy for modifying α-syn-associated pathology in PD.
Abstract
Background Post-translational modifications, particularly SUMOylation, plays a crucial role in α-synuclein (α-syn) aggregation, a key pathological feature of Parkinson’s disease (PD). Curcumin, a natural polyphenol, has shown neuroprotective potential, but its effects on SUMOylation-related signaling in PD remain unclear. Objective This study aimed to investigate whether curcumin modulates α-syn SUMOylation and to elucidate the underlying molecular mechanisms in PD model mice. Methods A PD model was established in male C57BL/6 mice via unilateral intrastriatal injection of α-syn preformed fibrils (PFFs). Six months after α-syn PFFs injection, mice were treated intravenously with curcumin (25 mg/kg/day) or vehicle for 1 month. Behavioral tests (open field, rotarod) assessed motor function. Neuropathology was evaluated by immunohistochemistry and western blotting for tyrosine hydroxylase (TH), phosphorylated α-syn (p-syn), SUMOylation pathway components (SUMO1, SAE2, UBC9, PIAS1/2), and ubiquitin. Striatal dopamine levels were measured by HPLC. Results Curcumin treatment ameliorated motor deficits and anxiety-like behaviors in PD mice. It partially preserved dopaminergic neurons and reduced p-syn aggregation in the substantia nigra, accompanied by increased striatal dopamine levels. Mechanistically, curcumin was associated with reduced SUMO1 and increased ubiquitin levels, suggesting modulation of SUMOylation-related signaling. Among SUMOylation enzymes, UBC9 expression was decreased, whereas E1 (SAE2) and E3 (PIAS1/2) components were not substantially affected. Conclusion Our findings demonstrated that curcumin exerted neuroprotective effects in a PD model by attenuating α-syn pathology. The protective mechanism involves the inhibition of α-syn SUMOylation, primarily through the downregulation of the UBC9 enzyme. This study identifies UBC9-mediated SUMOylation as a potential target for curcumin and highlight a promising strategy for modifying α-syn-associated pathology in PD.
Neuroprotective effects of statins in Parkinson’s disease (PD) remain uncertain, and their activity in genetic α-synuclein (αSyn) disease models has been insufficiently characterized. We evaluated atorvastatin (ATO) in a mouse model with nigral overexpression of human A53T-mutant αSyn. Mice received ATO by oral gavage at 10 mg/kg/day for 5 weeks and were assessed using behavioral testing, neuropathological assessment, brain transcriptomics, and molecular docking. ATO inhibited cholesterol biosynthesis-related transcriptional programs and broadly remodeled lipid metabolism-associated networks, but did not lead to functional or histopathological benefit. ATO did not ameliorate motor deficits, restore dopaminergic markers, or reduce αSyn protein levels or pSer129-αSyn immunoreactivity. Transcriptomic analysis further showed that ATO failed to reverse the core disease-associated signature induced by A53T αSyn overexpression and instead increased SNCA mRNA. Targeted RNA-seq and western blot analyses showed no parallel increase in Prkn, Gba1, or Lamp2 transcript abundance or in PARKIN, GBA1, or LAMP2A protein expression. Molecular docking, used here as an exploratory structural comparison, suggested a relatively weak predicted interaction between ATO and αSyn when compared with several other statins and provided supportive context for the lack of efficacy. Overall, our findings indicate limited efficacy of ATO in this αSyn-driven setting and support further comparative evaluation of individual statins across complementary PD models.
Li-Jian Wei, Jun-Kai Hua, Shu Tang et al.· Neurotoxicity research· 0 citations
Background/aim Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons and pathological aggregation of α-synuclein (α-syn), leading to significant motor and cognitive impairments. Kisspeptin-54 (KP-54), a neuropeptide primarily involved in reproductive regulation, has recently been implicated in neurorestorative processes, with emerging evidence suggesting beneficial effects on locomotor activity and cognitive function. However, its therapeutic potential in PD has not yet been fully investigated. This study aimed to evaluate the therapeutic efficacy of chronic nasal KP-54 administration in a 6-hydroxydopamine (6-OHDA) rat model of PD, focusing on motor and cognitive outcomes, hippocampal synaptic plasticity, and α-syn pathology. Materials and methods Adult Sprague–Dawley rats underwent unilateral 6-OHDA injections into the medial forebrain bundle to induce dopaminergic degeneration. Beginning 3 weeks after lesion induction, animals received daily nasal KP-54 or vehicle treatment for an additional 3 weeks. Motor performance was assessed using the catalepsy, beam balance, and open field tests, whereas cognitive function was evaluated using the Y-maze and object location test. Baseline assessments were conducted on day 0 prior to lesion formation. Electrophysiological recordings obtained from the hippocampal CA1 region were used to assess synaptic plasticity. Dopaminergic neuron survival and α-syn accumulation in the substantia nigra and hippocampus were quantified by immunofluorescence analysis. Results Chronic nasal KP-54 significantly ameliorated motor and cognitive deficits induced by 6-OHDA. KP-54 restored hippocampal synaptic plasticity, enhanced the survival of tyrosine hydroxylase-positive dopaminergic neurons, and reduced α-syn accumulation in both the substantia nigra and hippocampus. Conclusion The findings indicate that nasal KP-54 administration exerts neurorestorative effects in a 6-OHDA rat model of PD by preserving dopaminergic neurons, improving synaptic function, and attenuating pathological α-syn aggregation. These results position KP-54 as a promising candidate for disease-modifying therapy in Parkinson’s disease.
Ayşegül Gemici Sinen, E. Savran, Okyanus Bora Güleç et al.· Turkish Journal of Medical S...· 0 citations
Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. This study aimed to elucidate the dynamic interplay between these pathological pathways in a rotenone-induced rat model of PD. Adult male Wistar rats were chronically treated with rotenone. Behavioral assessments included Rotarod, Open Field, Rotating Pole, and Cylinder tests. On days 7, 14, and 21, gene expression levels of key markers including α-synuclein, NLRP3 inflammasome components (NLRP3, ASC), inflammatory cytokines (IL-1β, TNF-α, IL-6), upstream signaling molecules (TLR4, NF-κB), antioxidant defense factors (Nrf2, HO-1), apoptotic regulators (Bax, Bcl-2, Caspase-3), and tyrosine hydroxylase (TH) were quantified via qPCR. Crucially, protein abundance for all major markers was validated using ELISA, alongside biochemical assessment of oxidative stress markers (MDA and SOD). Rotenone treatment caused a progressive decline in motor performance across all behavioral assays (p < 0.001), including reduced rotarod latency, decreased open field distance, increased pole test latency, and heightened cylinder asymmetry. The PD group exhibited significant time-dependent increases in α-synuclein, TLR4, NF-κB, NLRP3, ASC, IL-1β, IL-6, TNF-α, Bax, Caspase-3, and MDA levels. Conversely, expression levels of Nrf2, HO-1, Bcl-2, and SOD activity showed marked decreases (p < 0.01). Finally, TH expression decreased progressively, reaching roughly 50% of control levels at day 21. Correlation analysis confirmed strong links between α-synuclein accumulation, inflammation, oxidative damage, and neuronal loss. These findings suggest a synergistic pathogenic cascade where α-synuclein accumulation contributes to neuroinflammation and oxidative stress, suppressing antioxidant defenses and activating apoptotic pathways, ultimately leading to dopaminergic neuron death and severe motor dysfunction.
Homa Vali Pour, M. Alfateh, Sanaz Mirzayan Shanjani et al.· Biochemical and Biophysical...· 0 citations
Parkinson's disease (PD) remains a neurodegenerative disorder without effective disease-modifying therapies, largely due to its multifactorial pathogenesis. We report that the natural flavonoid Astragalin (AST) concurrently addresses three core pathological processes in PD, namely dopaminergic neuron degeneration, α-synucleinopathy, and neuroinflammation, through coordinated modulation of interconnected molecular pathways. In both subacute MPTP- and chronic rotenone-induced murine PD models, AST preserved 85% of nigral tyrosine hydroxylase-positive neurons, fully prevented motor deficits, and suppressed phosphorylated α-synuclein (α-Syn) accumulation and Lewy body-like inclusion formation. Mechanistically, AST activated the BDNF-TrkB/AKT pro-survival pathway, enhanced NRF2-mediated antioxidant defense, and suppressed neuroinflammatory cascades by dual inhibition of Notch1/HES-1 and COP1-C/EBPβ signaling, leading to attenuated microglial and astrocytic activation. These findings position AST as a promising multi-target therapeutic neuroprotective candidate with disease-modifying potential, providing a structural scaffold for developing combination-inspired anti-PD strategies.
Jun Wang, Jie-Yu He, Qin Huang et al.· Free Radical Biology & Medic...· 0 citations
This review focuses on translational insights linking α-syn pathology to dysregulated stress-response and protein quality-control pathways, intending to identify potential targets for disease-modifying intervention.
Swaprakash Paul, Abhideep Roy, Pallab Bhattacharya et al.· Current Pharmacology Reports· 0 citations
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized pathologically by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies, which predominantly consist of misfolded α-synuclein (α-Syn) aggregates. Recent advances have highlighted the critical role of the interplay between α-Syn and lysosomal function, termed the α-Syn-lysosome axis, as a central mechanism underlying PD pathogenesis. This review systematically summarizes the molecular mechanisms driving α-Syn aggregation and the lysosomal dysfunction contributing to impaired autophagy-lysosome pathway (ALP) activity. We further discuss emerging therapeutic strategies targeting this axis to restore lysosomal function and mitigate α-Syn toxicity. By integrating the latest findings from molecular biology, cell biology, and preclinical studies, this article aims to elucidate the complex regulatory network of the α-Syn-lysosome axis and provide a theoretical foundation for the development of novel therapeutic interventions for PD.
