Mouse Model Of Parkinson's Disease Research Articles

Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice.

Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester-enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast-scan cyclic voltammetry), tissue dopamine levels (gas chromatography-mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow-up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease.

TMEM16F regulates pathologic α-synuclein secretion and spread in cellular and mouse models of Parkinson's disease.

One of the main hallmarks of Parkinson's disease (PD) pathology is the spread of the aggregate-prone protein α-synuclein (α-syn), which can be detected in the plasma and cerebrospinal fluid of patients as well as in the extracellular environment of neuronal cells. The secreted α-syn can exhibit "prion-like" behavior and transmission to naïve cells can promote conformational changes and pathology. The precise role of plasma membrane proteins in the pathologic process of α-syn is yet to be fully resolved. The TMEM16 family of lipid scramblases and ion channels has been recently associated with cancer and infectious diseases but is less known for its role in aging-related diseases. To elucidate the role of TMEM16F in α-syn spread, we transduced neurons derived from TMEM16F knockout mice with a reporter system that enables the distinction between donor and recipient neurons of pathologic α-synA53T. We found that the spread of α-synA53T was reduced in neurons derived from TMEM16F-knockout mice. These findings were recapitulated invivo in a mouse model of PD, where attenuated α-synA53T spread was observed when TMEM16F was ablated. Moreover, we identified a single nucleotide polymorphism in TMEM16F of Ashkenazi Jewish PD patients resulting in a missense Ala703Ser mutation with enhanced lipid scramblase activity. This mutation is associated with altered regulation of α-synA53T extracellular secretion in cellular models of PD. Our study highlights TMEM16F as a novel regulator of α-syn spread and as a potential therapeutic target in synucleinopathies.

Decrease of KATP channel expression through D3 receptor-mediated GSK3β signaling alleviates levodopa-induced dyskinesia (LID) in Parkinson's disease mouse model

Decrease of KATP channel expression through D3 receptor-mediated GSK3β signaling alleviates levodopa-induced dyskinesia (LID) in Parkinson's disease mouse model

Cycloastragenol reduces microglial NLRP3 inflammasome activation in Parkinson's disease models by promoting autophagy and reducing Scrib-driven ROS

BackgroundIn Parkinson's disease (PD), microglial autophagy is crucial for the maintenance of cellular redox homeostasis. Meanwhile, cycloastragenol (CAG), a triterpenoid saponin and the principal active component of Astragalus, reduces the activation of NLRP3 inflammasomes. Nevertheless, the specific molecular mechanisms underlying the CAG-mitigated microglial neuroinflammation remains obscure in PD. PurposeThis study explored the role of CAG in the activation of microglial NLRP3 inflammasome and the mechanisms underlying its therapeutic potential for PD treatment. Study designThe effect of CAG was assessed in α-Syn-induced primary microglia and PD models. MethodsAAV1/2-hsyn-SNCA (A53T) was stereo-injected into the striatum of mice to induce PD models and CAG was orally administered. The mice underwent quantitative 4D proteomics analysis and behavioral assessments. The primary microglia and neuron cultures were analyzed by western blotting, immunofluorescence, transmission electron microscopy, etc. ResultsCAG reduced phagocytosis-induced reactive oxygen species (ROS) by suppressing the microglial Scribble (Scrib) and p22phox expression. Concurrently, CAG enhanced autophagy, promoted α-Syn clearance, and reduced mitochondrial damage. These synergistic effects downregulated NLRP3 inflammasome activation, in turn reducing gasdermin D cleavage, caspase-1 activation, and the release of interleukin-1β and interleukin-18. Further investigation revealed that CAG shielded neurons from α-Syn toxicity, thus attenuating behavioral impairments observed in the mouse PD model. ConclusionCAG mitigates neuroinflammation by inhibiting ROS-induced NLRP3 inflammasome activation in microglia via promoting microglial autophagy and reducing the activity of Scrib-associated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which signifies a promising alternative approach to PD management.

Ablation of NAMPT in dopaminergic neurons leads to neurodegeneration and induces Parkinson’s disease in mouse

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the salvaging synthesize pathway of nicotinamide adenine dinucleotide (NAD). The neuroprotective roles of NAMPT on neurodegeneration have been explored in aging brain and Alzheimer’s Disease. However, its roles in Parkinson’s Disease (PD) remain to be elucidated. We found that the dopaminergic neurons in substantia nigra expressed higher levels of NAMPT than the other types of neurons. Using conditional knockout of the Nampt gene in dopaminergic neurons and utilizing a NAMPT inhibitor in the substantia nigra of mice, we found that the NAMPT deficiency triggered the time-dependent loss of dopaminergic neurons, the impairment of the dopamine nigrostriatal pathway, and the development of PD-like motor dysfunction. In the rotenone-induced PD mouse model, nicotinamide ribose (NR), a precursor of NAD, rescued the loss of dopaminergic neurons, the impairment of dopamine nigrostriatal pathway, and mitigated PD-like motor dysfunction. In SH-SY5Y cells, NAD suppression induced the accumulation of reactive oxygen species (ROS), mitochondrial impairment, and cell death, which was reversed by N-acetyl cysteine, an antioxidant and ROS scavenger. Rotenone decreased NAD level, induced the accumulation of ROS and the impairment of mitochondria, which was reversed by NR. In summary, our findings show that the ablation of NAMPT in dopaminergic neurons leads to neurodegeneration and contributes to the development of PD. The NAD precursors have the potential to protect the degeneration of dopaminergic neurons, and offering a therapeutic approach for the treatment of PD.

α-synuclein overexpression and the microbiome shape the gut and brain metabolome in mice

Pathological forms of α-synuclein contribute to synucleinopathies, including Parkinson’s disease (PD). Most cases of PD arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms in animal models. We quantitatively profiled nearly 630 metabolites in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice, compared to wild-type (WT) animals, and comparing germ-free (GF) to specific pathogen-free (SPF) animals (n = 5 WT-SPF; n = 6 ASO-SPF; n = 6 WT-GF; n = 6 ASO-GF). Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. The microbial metabolite trimethylamine N-oxide (TMAO) strongly correlates from the gut to the plasma to the brain in mice, notable since TMAO is elevated in the blood and cerebrospinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and microbiome in a mouse model of PD.

Effects of puerarin on gait disturbance in a 6-hydroxydopamine mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder caused by dopamine (DA) neuronal dysfunction. Although DA agonists and N-methyl-D-aspartate receptor (NMDAR) antagonists are used to treat PD, chronic use causes severe side effects. Puerarin (PUE) is a natural bioactive compound that affects the DA system; however, its effect on PD-associated motor functions is unknown. Therefore, we investigated whether PUE treatment in a 6-hydroxydopamine (6-OHDA) PD mouse model affects motor dysfunction. Adult male ICR mice received unilateral 6-OHDA microinfusion into the right medial forebrain bundle. After a 2-week recovery period, PUE (20 or 50mg/kg) or the vehicle (saline, VEH) was administered intraperitoneally once daily for 21 days. Motor dysfunction was assessed using the locomotion, gait cycle, and rotation tests. Local field potentials (LFPs) were measured in the substantia nigra compacta (SNc), striatum (STR), subthalamic nucleus (STN), and primary motor cortex. 6-OHDA-lesioned PD mice showed increased gait cycle disturbance and unidirectional rotation. PUE treatment ameliorated the gait cycle disturbance, but not unidirectional rotation of PD mice. These effects differed with DA agonist treatment (which improved PD symptoms) and NMDAR antagonist treatment (which aggravated PD symptoms). Moreover, locomotion was increased only in NMDAR antagonist treatment. PUE treatment induced no changes in the attenuated LFP of the beta wave in the STR and STN, and SNc-STN delta-wave coherence was shown in PD animals. This study suggests that PUE is a beneficial co-therapeutic agent for alleviating gait cycle disturbance in PD symptoms.

CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease

Cereblon (CRBN) is a substrate recruiter for CRL4CRBN E3 ubiquitin ligase system playing a plethora of pivotal roles for biological systems. Here, we identified DNAJB1 (DJ1) as endogenous substrate of CRBN and report how CRBN influences the aggregation and toxicity of alpha-synuclein (α-SYN) via modulation of DJ1. CRBN interferes with molecular activities of DJ1 in vitro, in cells, and in vivo resulting in a reduced disaggregation of α-SYN fibrils, increased formation of preformed fibrils (PFFs) of α-SYN, and high susceptibility of mice to MPTP and PFF-induced neurotoxicity. Depletion of Crbn improves the behavioral and biochemical responses of mice towards neurotoxic insult. Finally, we designed a peptide inhibitor to inhibit the recruitment of DJ1 to CRBN for ubiquitination, resulting in an enhanced supply of DJ1 to counteract the toxicity of aggregated α-SYN. Our data has important implications for development of CRBN-targeting therapies that could prevent or delay progression of neurodegenerative synucleinopathy.

LncRNA MALAT1 facilitates Parkinson's disease progression by increasing SOCS3 promoter methylation.

Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been shown to be involved in Parkinson's disease (PD) progression, but its mechanism needs to be further explored. Mice were injected with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD mice models, and BV2 cells were treated with lipopolysaccharides (LPS) to mimic PD cell models. MALAT1 expression and suppressor of cytokine signaling 3 (SOCS3) protein level were examined using quantitative real-time PCR and western blot, respectively. Cell functions were tested by cell counting kit 8 assay and flow cytometry. The interaction between MALAT1 and SOCS3 was confirmed using RNA pull-down and RIP assays. MALAT1 was upregulated in MPTP-induced PD mice and LPS-induced BV2 cells. Silencing of MALAT1 increased viability, while inhibited apoptosis and inflammation in LPS-induced BV2 cells. Besides, MALAT1 enhanced the SOCS3 promoter methylation to decrease its expression by recruiting DNMT1, DNMT3A and DNMT3B. Furthermore, SOCS3 knockdown eliminated sh-MALAT1-mediated the inhibition effect on LPS-induced BV2 cell injury. In vivo, MALAT1 silencing ameliorated neurological impairment and neuroinflammation in MPTP-induced PD mice. Our data revealed that MALAT1 worsened PD processes via inhibiting SOCS3 expression by increasing its promoter methylation.

Targeting the Sirtuin–1/PPAR–Gamma Axis, RAGE/HMGB1/NF-κB Signaling, and the Mitochondrial Functions by Canagliflozin Augments the Protective Effects of Levodopa/Carbidopa in Rotenone-Induced Parkinson’s Disease

Background and Objectives: Parkinson’s disease (PD) is a pathological state characterized by a combined set of abnormal movements including slow motion, resting tremors, profound stiffness of skeletal muscles, or obvious abnormalities in posture and gait, together with significant behavioral changes. Until now, no single therapeutic modality was able to provide a complete cure for PD. This work was a trial to assess the immunomodulatory effects of canagliflozin with or without levodopa/carbidopa on rotenone-induced parkinsonism in Balb/c mice. Materials and Methods: In a mouse model of PD, the effect of canagliflozin with or without levodopa/carbidopa was assessed at the behavioral, biochemical, and histopathological levels. Results: The combination of levodopa/carbidopa and canagliflozin significantly mitigated the changes induced by rotenone administration regarding the behavioral tests, striatal dopamine, antioxidant status, Nrf2 content, SIRT–1/PPAR–gamma axis, RAGE/HMGB1/NF-κB signaling, and mitochondrial dysfunction; abrogated the neuroinflammatory responses, and alleviated the histomorphologic changes induced by rotenone administration relative to the groups that received either levodopa/carbidopa or canagliflozin alone. Conclusions: Canagliflozin may represent a new adjuvant therapeutic agent that may add value to the combatting effects of levodopa/carbidopa against the pathological effects of PD.

Targeting serum response factor (SRF) deactivates ΔFosB and mitigates Levodopa-induced dyskinesia in a mouse model of Parkinson's disease.

L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the preferred treatment for Parkinson's Disease (PD) and is considered the gold standard. However, prolonged use of L-DOPA in patients can result in involuntary movements known as Levodopa-induced dyskinesia (LID), which includes uncontrollable dystonia affecting the trunk, limbs, and face. The role of ΔFosB protein, a truncated splice variant of the FosB gene, in LID has been acknowledged, but its underlying mechanism has remained elusive. Here, using a mouse model of Parkinson's disease treated with chronic levodopa we demonstrate that serum response factor (SRF) binds to the FosB promoter, thereby activating FosB expression and levodopa induced-dyskinetic movements. Western blot analysis demonstrates a significant increase in SRF expression in the dyskinetic group compared to the control group. Knocking down SRF significantly reduced abnormal involuntary movements (AIMS) and ΔFosB expression compared to the control. Conversely, overexpression of SRF led to an increase in ΔFosB expression and worsened levodopa-induced dyskinesia. To shed light on the regulatory role of the Akt signaling pathway in this phenomenon, we administered the Akt agonist SC79 to PD mouse models via intraperitoneal injection, followed by L-DOPA administration. The expression of SRF, ΔFosB, and phosphorylated Akt (p-Akt) significantly increased in this group compared to the group receiving normal saline to signify that these happen through Akt signaling pathway. Collectively, our findings identify a promising therapeutic target for addressing levodopa-induced dyskinesia.

The role of interferon signaling in neurodegeneration and neuropsychiatric disorders.

Recent advances in transcriptomics research have uncovered heightened interferon (IFN) responses in neurodegenerative diseases including Alzheimer's disease, primary tauopathy, Parkinson's disease, TDP-43 proteinopathy, and related mouse models. Augmented IFN signaling is now relatively well established for microglia in these contexts, but emerging work has highlighted a novel role for IFN-responsive T cells in the brain and peripheral blood in some types of neurodegeneration. These findings complement a body of literature implicating dysregulated IFN signaling in neuropsychiatric disorders including major depression and post-traumatic stress disorder. In this review, we will characterize and integrate advances in our understanding of IFN responses in neurodegenerative and neuropsychiatric disease, discuss how sex and ancestry modulate the IFN response, and examine potential mechanistic explanations for the upregulation of antiviral-like IFN signaling pathways in these seemingly non-viral neurological and psychiatric disorders.

Environmental Enrichment Attenuates Reproductive Adversity in a Mouse Model of Parkinson Disease

Environmental enrichment is the provision of different substrates to mimic an animal’s natural environment and encourage natural, species-specific behavior. However, the use of enrichment to improve breeding efficiency in mouse models for neurologic conditions is not well described. There are reports that diminished environmental stimuli and chronic isolation can result in the early expression of the Parkinson phenotype in mice with a genetic predisposition to the disease. In this study, we compared the provision of crinkle paper, DietGel, and their combination on reproductive parameters in B6.Cg-Tg(THY1-SNCA*A53T)M53Sud mice. We found that enhanced enrichment combined with enhanced nutrition increased dam weight and decreased the interlitter intervals. In addition, enhanced enrichment increased the production index, number of pups born, pups weaned, and the percent survival of pups. This study underscores the importance of incorporating enrichment to enhance the reproductive parameters in mice that are models of Parkinson disease.

Dopamine neuron dysfunction and loss in the PrknR275W mouse model of juvenile parkinsonism.

Mutations in the PRKN gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson's disease mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. To this end, we created a knock-in mouse carrying the homozygous PrknR275W mutation, which is the missense mutation with the highest allelic frequency in PRKN patients. We evaluated the anatomical and functional integrity of the nigrostriatal dopamine (DA) pathway, as well as motor behaviour in PrknR275W mice of both sexes. We report here that PrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that the PrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new Parkinson's disease model in which to study causative mechanisms of the disease and test therapeutic strategies.

Quantitative systems pharmacology model of α-synuclein pathology in Parkinson's disease-like mouse for investigation of passive immunotherapy mechanisms.

The main pathophysiological hallmark of Parkinson's disease (PD) is the accumulation of aggregated alpha-synuclein (αSyn). Microglial activation is an early event in PD and may play a key role in pathological αSyn aggregation and transmission, as well as in clearance of αSyn and immunotherapy efficacy. Our aim was to investigate how different proposed mechanisms of anti-αSyn immunotherapy may contribute to pathology reduction in various PD-like mouse models. Our mechanistic model of PD pathology in mouse includes αSyn production, aggregation, degradation and distribution in neurons, secretion into interstitial fluid, internalization, and subsequent clearance by neurons and microglia. It describes the influence of neuroinflammation on PD pathogenesis and dopaminergic neurodegeneration. Multiple data from mouse PD models were used for calibration and validation. Simulations of anti-αSyn passive immunotherapy adequately reproduce preclinical data and suggest that (1) immunotherapy is efficient in the reduction of aggregated αSyn in various models of PD-like pathology; (2) prevention of aSyn spread only does not reduce the pathology; (3) a decrease in microglial inflammatory activation and aSyn aggregation may be alternative therapy approaches in PD-like pathology.

Chondroitin sulfate modulates oxidative stress and inflammation in the substantia nigra via gut microbiota regulation: Mechanistic insights into Parkinson's disease treatment

Hydrogen sulfide (H2S) is a bioactive gas with potential neuroprotective properties. This study explores the therapeutic efficacy of chondroitin sulfate (CS) in a Parkinson's disease (PD) mouse model by evaluating its impact on behavior, gut microbiota composition, substantia nigra (SN) pathology, oxidative stress, and inflammation. Behavioral tests indicate that CS improves cognitive function and learning abilities in PD mice. Gut microbiota analysis and fecal H2S content measurement reveal that CS fosters the growth of Desulfovibrio and boosts H2S production, respectively. Further examination shows that CS treatment enhances antioxidant defenses, reduces inducible nitric oxide synthase (iNOS)-mediated inflammation, and alleviates PD-related pathology and α-synuclein overexpression in the SN. These findings suggest that CS modulates the gut microbiota and its metabolic product, H2S, potentially improving PD symptoms through the gut-brain axis.

Vagus nerve stimulation with a small total charge transfer improves motor behavior and reduces neuroinflammation in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Conventional treatments are ineffective in reversing disease progression. Recently, the therapeutic and rehabilitation potential of vagus nerve stimulation (VNS) in PD has been explored. However, the underlying mechanisms remain largely unknown. In this study, we investigated the neuroprotective effects of VNS in a lateral lesioned mice model of PD. Excluding controls, experimental mice received cuff electrode implantation on the left vagus nerve and 6-hydroxydopamine administration into the bilateral striatum. After ten days, electrical stimulation was delivered for 11 consecutive days onto PD animals. Behavioral tests were performed after stimulation. The expression of TH, Iba-1, GFAP, adrenergic receptors and cytokines in the SN and striatum was detected by immunofluorescence or western blotting. The activity of noradrenergic neurons in the locus coeruleus (LC) was also measured. Our results suggest that VNS improved behavioral performance in rod rotation, open field tests and pole-climbing tests in PD mice, accompanied by a decrease in the loss of dopaminergic neurons in the SN and increased TH expression in the striatum. Neuroinflammation-related factors, such as GFAP, Iba-1, TNF-α and IL-1β were also suppressed in PD mice after VNS compared to those without treatment. Furthermore, the proportion of c-Fos-positive noradrenergic neurons in the LC increased when animals received VNS. Additionally, the expression of the adrenergic receptor of α1BR was also upregulated after VNS compared to PD mice. In conclusion, VNS has potential as a novel PD therapy for neuroprotective effects, and indicate that activation of norepinephric neurons in LC may plays an important role in VNS treatment for PD.

Shisandra Decoction Alleviates Parkinson's Disease Symptoms in a Mouse Model Through PI3K/AKT/mTOR Signalling Pathway.

The present study aimed to characterize neuroprotective effects of Schisandra Decoction (Sch D) treatment in a mouse model of Parkinson's disease (PD), and to explore underlying mechanisms focused on the mammalian target of rapamycin (mTOR) signaling pathway. 50 male C57 BL/6 mice were randomly assigned to either control (n = 10) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model (n = 40) groups. PD mice were further divided into four groups of ten mice each: MPTP group, LY294002 group, Sch D group, and LY2940002 + Sch D group. Mice from each group were assessed in pole climbing, rotary rod and open field tests. Brain Tyrosine hydroxylase (TH) protein was observed using immunohistochemistry. mRNA levels of PTEN, PI3K and LC3 in brain tissue were measured using RT-PCR. Protein levels of PTEN, PI3K, Akt, p-Akt, mTOR, p-mTOR, p70s6K, p62, LC3II / I, α-synuclein (α-syn), TH in brain tissue were assessed by Western blotting (WB). In behavioral tests, PD mice treated with Sch D showed reduced pole climbing time, longer rotarod duration, and greater distance traveled. In terms of neuroprotection, PD mice in the Sch D group exhibited higher levels of TH protein and enhanced α-syn clearance. Regarding autophagy, compared to the control group, mice in the MPTP group had elevated PTEN protein expression, which inhibited PI3K, p-AKT/AKT, and p-mTOR/mTOR protein levels, decreased LC3II/I protein expression, and increased P62 protein expression. Treatment with Sch D reversed these effects. Sch D reduces α-syn aggregation in the brains of MPTP-induced PD model mice, exerts neuroprotective effects, and improves motor function. Additionally, Sch D inhibits autophagy through the PI3K/AKT/mTOR pathway. The neuroprotective effect of Sch D may involve the suppression of abnormal autophagy and its antioxidant properties, which indirectly reduces α-syn accumulation. Future studies should assess the impact of Sch D on oxidative stress markers to evaluate its antioxidant effects.

The tolerable upper intake level of manganese alleviates Parkinson-like motor performance and neuronal loss by activating mitophagy

Manganese (Mn2+) is among the indispensable trace elements required by the human body, but high-dose Mn2+ exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn2+ has been established for normal individuals in different countries. However, whether the UL of Mn2+ is suitable for the patients of Parkinson's disease (PD) is unclear.Here, we found unexpectedly that the dietary UL of Mn2+ supplement enhanced mitophagy through the PINK1/parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn2+ promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn2+ directly elevated the activity of mitochondrial superoxide dismutase (MnSOD), which contributed to the clearance of reactive oxygen species (ROS), restored dopaminergic and motor functions in the MPTP-induced PD mouse model. Similar results were also observed in SH-SY5Y cells, whereas knockdown parkin using siRNA or application of mitophagy inhibitors (Mdivi-1 or cyclosporine A), abolished the neuroprotective effects of Mn2+.These findings demonstrate that the dietary UL of Mn2+ is protective for the MPTP-induced Parkinson-like lesions with the mechanisms involving the activation of mitophagy, suggesting potential intervention of PD by moderately increasing dietary Mn2+ intake.

Lactiplantibacillus plantarum SG5 inhibits neuroinflammation in MPTP-induced PD mice through GLP-1/PGC-1α pathway

Mounting evidence suggests that alterations in gut microbial composition play an active role in the pathogenesis of Parkinson's disease (PD). Probiotics are believed to modulate gut microbiota, potentially influencing PD development through the microbiota-gut-brain axis. However, the potential beneficial effects of Lactiplantibacillus plantarum SG5 (formerly known as Lactobacillus plantarum, abbreviated as L. plantarum) on PD and its underlying mechanisms remain unclear. In this study, we employed immunofluorescence, Western blotting, ELISA, and 16S rRNA gene sequencing to investigate the neuroprotective effects of L. plantarum SG5 against neuroinflammation in an MPTP-induced PD model and to explore the underlying mechanisms. Our results demonstrated that L. plantarum SG5 ameliorated MPTP-induced motor deficits, dopaminergic neuron loss, and elevated α-synuclein protein levels. Furthermore, SG5 inhibited MPTP-triggered overactivation of microglia and astrocytes in the substantia nigra (SN), attenuated disruption of both blood-brain and intestinal barriers, and suppressed the release of inflammatory factors in the colon and SN. Notably, SG5 modulated the composition and structure of the gut microbiota in mice. The MPTP-induced decrease in colonic GLP-1 secretion was reversed by SG5 treatment, accompanied by increased expression of GLP-1R and PGC-1α in the SN. Importantly, the GLP-1R antagonist Exendin 9–39 and PGC-1α inhibitor SR18292 attenuated the protective effects of SG5 in PD mice. In conclusion, we demonstrate a neuroprotective role of L. plantarum SG5 in the MPTP-induced PD mouse model, which likely involves modulation of the gut microbiota and, significantly, the GLP-1/PGC-1α signaling pathway.