Spatial lipidomics identifies α-synuclein-induced lipid changes in an AAV-induced Parkinsonian mouse model.

This study describes the case of an 83-year-old man with long-standing hypertension, urinary dysfunction, and constipation. Annual 24-h ambulatory blood pressure monitoring revealed increased blood pressure variability and reduced nocturnal dipping. One year earlier, exaggerated blood pressure fluctuations and postprandial hypotension had emerged, which persisted despite the reduced use of antihypertensive medication. The tests confirmed orthostatic and postprandial hypotension and low heart rate variability, indicating autonomic dysfunction. Cognitive function was preserved and the patient's physical function remained intact. Imaging findings suggested prodromal dementia with Lewy bodies, although the typical symptoms of this disease were absent. Blood pressure control became difficult and stabilized after development of chronic renal failure. The patient died of colon cancer and renal failure. An autopsy revealed widespread α-synuclein in the peripheral nerves and cardiac autonomic degeneration, with mild loss of neurons in the substantia nigra but severe degeneration in the locus coeruleus. Lewy body pathology slowly spreads to the hippocampus and neocortex. These findings demonstrated that exaggerated BP variability in ambulatory blood pressure monitoring could be early marker of the progression of autonomic dysfunction, caused by prodromal body-first-type of α-synucleinopathy, before appearance of neurological symptoms.

Clinical and cognitive profile of nigral iron content in children with ADHD.

Valsartan promotes neuroprotection in Parkinson's disease via epigenetic modulation and activation of the ASCL1/Nurr1 pathway.

Causal relationships between plasma lipidomics, trace elements, cerebrospinal fluid metabolites, and Parkinson's disease using Mendelian randomization.

The H2S donor sulforaphane inhibits NLRP3 inflammasome activation by inducing mitochondrial autophagy and mitigating CBS-H2S axis damage in in-vitro and in-vivo models of Parkinson's disease.

Effects of neuromelanin buildup in rodent nigral dopamine neurons: implications for sex-biased vulnerability in Parkinson's disease.

Impaired autophagy from TRPV4 activation drives α-synuclein pathology in a Parkinson's disease model: A toxicological insight.

Quantitative susceptibility mapping (QSM) measures the intrinsic magnetic susceptibility of tissues. Because susceptibility values are inherently relative rather than absolute, referencing to a region of interest (ROI) is commonly employed to mitigate intersubject and acquisition-related variability. To validate the feasibility and robustness of a differential ROI reference method in QSM using both digital phantom and invivo data, particularly for deep gray matter susceptibility analysis. In the digital phantom study, susceptibility values in the caudate nucleus were assessed with and without differential referencing across various simulation conditions (slab widths, brain mask erosion levels, air susceptibility). In the invivo study, susceptibility differences between 16 patients with Parkinson's disease (PD) and 16 controls were compared across multiple deep gray matter ROIs under variable acquisition parameters. A one-way ANOVA statistical test was used in the invivo study with multiple-comparison correction via the Benjamini-Hochberg false discovery rate (FDR-BH), with significance set at p < 0.05. In this study, "accuracy" refers specifically to the phantom study where ground-truth susceptibility values are known. Invivo, where such ground truth is unavailable, "robustness" and "group-discrimination sensitivity" are used as surrogate indicators of accuracy. Robustness was evaluated by the consistency of susceptibility differences across varying acquisition parameters, whereas group-discrimination sensitivity was evaluated by the ability to detect disease-related group differences between PD patients and controls. In the digital phantom study, the proposed method demonstrated stable susceptibility estimates across all conditions, with minimal deviation from true values when referencing anatomically adjacent ROIs. In the invivo study, referenced susceptibility values (e.g., substantia nigra minus putamen) yielded consistent and significant group differences across acquisition scenarios, whereas unreferenced values were more variable. The differential ROI reference method reduces susceptibility variability associated with acquisition and processing factors. This approach may offer a practical and pathology-resilient referencing alternative for deep brain analysis in neurodegenerative diseases.

Implications of cellular senescence in Parkinson's disease: Recent developments and future directions.

Gender-specific gene profiling in Drosophila sporadic model of Parkinson's disease.

Heterozygous (G603R) LRP10 mutation causes autosomal dominant Parkinson's disease (PD). Heterozygous Lrp10G603R/+ mice were prepared to unravel pathomechanisms underlying (G603R) Lrp10-induced death of substantia nigra (SN) dopaminergic neurons. Lrp10G603R/+ mouse exhibited PD movement deficits, neurodegeneration of SN dopaminergic cells and existence of SN phospho-α-synuclein-containing aggregates. Lrp10 was expressed in mouse SN dopaminergic neurons, and WT LRP10 exerted neuroprotection function on dopaminergic cells by repressing α-synuclein gene transcription and downregulating α-synuclein mRNA. (G603R) LRP10 failed to negatively regulate α-synuclein mRNA of dopaminergic neurons, and heterozygous (G603R) Lrp10 mutation elevated protein and mRNA of pathological α-synuclein or α-synuclein oligomers in SN dopaminergic cells of Lrp10G603R/+ mouse. Macroautophagy activator rapamycin reversed (G603R) Lrp10-induced increment of α-synuclein, death of SN dopaminergic cells and PD locomotor disability in Lrp10G603R/+ mouse. (G603R) Lrp10 upregulation of α-synuclein increased ER α-synuclein and activated ER stress and UPR, resulting in excitation of ER stress pro-apoptotic pathway in SN of Lrp10G603R/+ mouse. Upregulated α-synuclein within SN dopaminergic cells increased mitochondrial α-synuclein and induced mitochondrial detriment and oxidative insult in SN of Lrp10G603R/+ mouse. (G603R) Lrp10-evoked overexpression of Puma, Noxa or Bim and mitochondrial abnormality excited mitochondrial apoptotic process in SN of Lrp10G603R/+ mouse. Elevated α-synuclein oligomers excited NLRP3 inflammasome and microglia in SN of Lrp10G603R/+ mouse, leading to incremented IL-1β-, IL-18- or TNF-α-triggered MKK4-JNK-c-Jun/ATF-2 degeneration and RIPK1-RIPK3-MLKL necroptotic pathways. Our data propose that heterozygous loss-of-function (G603R) mutation of LRP10 debilitates WT LRP10-mediated downregulation of α-synuclein mRNA, leading to elevated α-synuclein-evoked neurodegeneration of SN dopaminergic cells and autosomal dominant PD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by aggregates of α-synuclein and the degeneration of dopaminergic neurons in the substantia nigra. Current pharmaceutical therapies mainly alleviate symptoms without halting disease progression. Evidence suggests that traditional plant-based interventions may serve as supplementary therapies by targeting oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. This review explores the neuroprotective properties of ten medicinal plants commonly used in traditional medicine: Bacopa monnieri, Curcuma longa, Mimosa pudica, Zingiber officinale, Ocimum sanctum, Emblica officinalis, Camellia sinensis, Cannabis sativa, Panax ginseng, and Withania somnifera. A systematic and comprehensive search of PubMed, Scopus, and Web of Science identified relevant in vitro, in vivo, and clinical studies. This study highlights the mechanisms by which plant-derived chemicals influence cellular pathways associated with PD, emphasising their therapeutic potential despite limited clinical validation. Studies have shown that bioactive compounds such as curcumin, bacoside, Epigallocatechin-3-gallate (EGCG), cannabidiol, ginsenosides, and withanolides exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects in PD models. Nanotechnology offers promising strategy to enhance the efficacy of herbal compounds, addressing challenges of poor solubility, rapid metabolism, low bioavailability, and restricted blood-brain barrier penetration. Nano-delivery systems including liposomes, polymeric nanoparticles, nanoemulsions, and metal nanoparticles can improve stability, brain targeting, controlled release, and cellular uptake of these bioactives, thereby enhancing therapeutic efficiency while reducing systemic toxicity. Green-synthesized plant-based nanoparticles further provide synergistic neuroprotective benefits, positioning phyto-nanomedicine as a multi-target approach for PD therapy. However, extensive clinical studies are required to confirm safety and effectiveness.

Parkinson's disease (PD) is a progressive neurodegenerative disorder traditionally characterized by dopaminergic neuronal loss in the substantia nigra and the accumulation of misfolded α-synuclein (α-syn) aggregates. While genetic susceptibility and environmental exposures are well-recognized contributors to PD, growing evidence indicates that disease initiation and progression may also involve peripheral mechanisms originating in the gastrointestinal (GI) tract. Early non-motor symptoms such as constipation, along with the presence of α-syn pathology in the enteric nervous system, have led to increasing interest in the gut-brain axis as a critical modulator of PD pathogenesis. Recent literatures reveal that gut microbiota dysbiosis can influence neurodegeneration through immune activation, intestinal barrier dysfunction, and altered production of microbial metabolites, including short-chain fatty acids, bile acids, lipopolysaccharides, and tryptophan-derived compounds. However, the precise molecular mechanisms by which these microbial factors modulate α-syn aggregation, propagation, and clearance remain incompletely understood. In this article, we review current clinical and experimental literature linking gut microbiota alterations to α-syn pathology, with particular emphasis on inflammatory signaling, microbial metabolites, and impaired proteostatic pathways that promote α-syn misfolding. We further integrate emerging concepts of "body-first" and "brain-first" PD subtypes and discuss proposed routes of α-syn transmission from the enteric to the central nervous system, including vagal, hematogenous, and immune-mediated pathways. By highlighting underexplored mechanistic connections between gut dysbiosis and α-syn biology, this review underscores the potential of microbiome-targeted strategies for early diagnosis and disease modification. A deeper understanding of gut-brain communication may ultimately enable personalized therapeutic approaches and reshape current paradigms of PD pathogenesis.

Gut microbiota dysbiosis contributes to Parkinson's disease (PD) pathology by altering dopamine metabolism in the gut-brain axis. Although probiotics and other functional strains have been proposed as microbiome-based interventions, few naturally occurring gut microbes show therapeutic potential for PD. Here, we isolated Enterococcus hirae QT4713 (QT4713) from the hypoxic, low-pressure Qinghai-Tibet Plateau (4713 m altitude). Whole-genome sequencing revealed that QT4713 harbors a tyrosine decarboxylase gene (TyrDc), enabling conversion of L-tyrosine to dopamine in vitro. In mice, QT4713 enhanced antioxidant enzyme activity, reduced inflammatory mediators, reshaped gut microbial composition, and promoted short-chain fatty acid production. Metabolomic analyses indicated activation of L-tyrosine metabolism, with increased L-DOPA and dopamine levels in the colon and feces, accompanied by improved motor performance. In an MPTP-induced PD mouse model, QT4713 alleviated motor and gastrointestinal dysfunction, reduced oxidative and inflammatory damage, and attenuated dopaminergic neuron loss. QT4713 also increased dopamine and tyrosine levels in the striatum. Extending beyond an acute toxin model, QT4713 partially rescued PD-like phenotypes in TMEM175 knockout mice, preserving tyrosine hydroxylase-positive neurons in the substantia nigra. Together, these findings suggest that QT4713 can mitigate gastrointestinal disturbances and other PD-related deficits, consistent with combined effects on catecholamine-related metabolism and gut microbiota remodeling.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by oxidative stress and neuroinflammation. Current treatments mainly provide symptomatic relief without altering disease progression. Tubeimoside-1 (TBMS1), a saponin compound with antioxidant and anti-inflammatory activity, has shown promise as a neuroprotective agent in experimental models. This study aimed to assess the neuroprotective efficacy of TBMS1 in reducing motor dysfunction, oxidative stress, and neuroinflammatory responses in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). Male Wistar rats were allocated into sham, lesion, and TBMS1-treated groups. TBMS1 (5 µM/kg) was administered intraperitoneally for four weeks. Behavioral evaluation was conducted using apomorphine-induced rotation tests. Histological and biochemical analyses measured dopaminergic integrity (Nissl and TH staining), oxidative stress markers (MDA, ROS, GSH, Nrf2), and neuroinflammation (Iba1 expression) via ELISA and immunohistochemistry. TBMS1 significantly reduced rotational behavior and partially restored striatal dopamine and DOPAC levels. It preserved dopaminergic neurons in the SNpc and mitigated oxidative stress by decreasing MDA and ROS while elevating GSH and Nrf2 levels. TBMS1 also reduced microglial activation, as shown by lower Iba1 expression. TBMS1 exerts notable neuroprotective effects in the 6-OHDA rat model of PD by improving motor function, limiting oxidative and inflammatory damage, and preserving dopaminergic neurons. These results suggest TBMS1 as a promising candidate for further therapeutic investigation in PD.

Parkinson's disease is a progressive and severe neurodegenerative disease with loss of dopaminergic neurons of substantia nigra. Sigma-1 receptor activation by ligand/agonist has shown neuroprotective effect in various diseases including Parkinson's disease. Present study aimed to investigate the neuroprotective potential of 1,3-di-o-tolylguanidine, a Sigma-1 receptor agonist in rat model of Parkinson's disease. Male Wistar rats underwent intraperitoneal administration of rotenone with simultaneous treatment of 1,3-di-o-tolylguanidine for 28 days. After 28 days, behavioural tests were conducted for assessing motor symptoms. Sigma 1 receptor, dopamine, alpha synuclein, IL-6, glutamate levels were measured in brain homogenate. Histopathological studies were performed for assessing neurodegeneration. Rotenone treated disease control group showed significant bradykinesia, impaired grip strength and motor incoordination compared to normal control group. Further, brain sigma 1 receptor, dopamine, alpha synuclein, IL-6, glutamate levels as well as histological features were significantly compromised. Treatment with 1,3-di-o-tolylguanidine significantly improved behavioural parameters, biochemical parameters and histological features in dose dependent manner. These findings suggest that 1,3-di-o-tolylguanidine has neuroprotective effects in rotenone-induced model of Parkinson's disease in rats.

Mitochondrial transplantation has emerged as a promising therapeutic strategy for neurological diseases associated with mitochondrial dysfunction. However, its application to central nervous system (CNS) disorders remains limited by the restrictive nature of the blood-brain barrier (BBB). Here, we report neutrophil-like mitochondria (nePM@Mito), engineered by coating isolated mitochondria with neutrophil plasma membranes to facilitate CNS delivery. By presenting neutrophil-derived surface adhesion molecules, nePM@Mito interact with endothelial receptors and recapitulate key features of neutrophil transendothelial migration, facilitating BBB crossing via endothelial exocytosis. In a mouse model of Parkinson's disease, intravenous administration of nePM@Mito leads to pronounced CNS accumulation and attenuation of oxidative stress. Delivered mitochondria restore mitochondrial function and increase tyrosine hydroxylase expression in dopaminergic neurons of the substantia nigra, resulting in elevated dopamine levels and improved motor performance. Notably, neutrophil membrane functionalization endows mitochondria with CNS-homing capability while preserving their intrinsic biological activity. The neutrophil-like mitochondrial delivery strategy provides a versatile platform for overcoming BBB limitations and offers a promising therapeutic approach for neurodegenerative diseases involving mitochondrial dysfunction.

ABSTRACT Background Agaricus bisporus contains bioactive proteins, including tyrosinase, which may influence dopaminergic metabolism. Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons driven by oxidative stress, neuroinflammation, and apoptosis. Objective To evaluate the neuroprotective effects of an Agaricus bisporus protein extract (ABE) and its mechanistic basis in an MPTP-induced mouse model of PD. Methods A tyrosinase-enriched protein fraction was isolated and administered orally to MPTP-treated mice for 20 days. Behavioral performance, dopaminergic markers, oxidative stress parameters, inflammatory mediators, and apoptosis-related proteins were assessed in the substantia nigra. Results ABE exhibited preserved tyrosinase activity after simulated gastrointestinal digestion. In vivo, ABE increased plasma L-DOPA and dopamine levels by ∼55% and ∼30%, respectively (p < 0.001 and p < 0.01), and significantly elevated nigral dopamine (p < 0.001) and AADC activity (p < 0.01). Motor deficits were attenuated, with reduced beam-walking errors (p < 0.001). Oxidative stress was mitigated, as evidenced by restoration of SOD and CAT activities (p < 0.001) and reduction of MDA, H₂O₂, and NO levels (p < 0.05). ABE suppressed neuroinflammation by decreasing NF-κB p65 expression (p < 0.001) and reducing IL-6, IL-1β, and TNF-α levels (p < 0.05). Apoptotic signaling was shifted toward cell survival, with increased Bcl-2 (p < 0.01) and decreased Bax and Bad expression (p < 0.01). Immunohistochemistry confirmed preservation of tyrosine hydroxylase – positive neurons (p < 0.001). Conclusion ABE exerts neuroprotective effects in MPTP-induced PD via tyrosinase-associated enhancement of dopaminergic metabolism, alongside antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Functional and microstructural biomarkers of repetitive mild head injury in a conscious momentum exchange mouse model.