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Journal of Biomedical Science Aug 2023Parkinson's disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental...
BACKGROUND
Parkinson's disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental and genetic aspects are involved in the pathogenesis of PD. Osmotin is a structural and functional homolog of adiponectin, which regulates the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) via adiponectin receptor 1 (AdipoR1), thus attenuating PD-associated pathology. Therefore, the current study investigated the neuroprotective effects of osmotin using in vitro and in vivo models of PD.
METHODS
The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and neuron-specific enolase promoter human alpha-synuclein (NSE-hαSyn) transgenic mouse models and 1-methyl-4-phenylpyridinium (MPP)- or alpha-synuclein A53T-treated cell models. MPTP was injected at a dose of 30 mg/kg/day for five days, and osmotin was injected twice a week at a dose of 15 mg/kg for five weeks. We performed behavioral tests and analyzed the biochemical and molecular changes in the substantia nigra pars compacta (SNpc) and the striatum.
RESULTS
Based on our study, osmotin mitigated MPTP- and α-synuclein-induced motor dysfunction by upregulating the nuclear receptor-related 1 protein (Nurr1) transcription factor and its downstream markers tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2). From a pathological perspective, osmotin ameliorated neuronal cell death and neuroinflammation by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, osmotin alleviated the accumulation of α-synuclein by promoting the AMPK/mammalian target of rapamycin (mTOR) autophagy signaling pathway. Finally, in nonmotor symptoms of PD, such as cognitive deficits, osmotin restored synaptic deficits, thereby improving cognitive impairment in MPTP- and α-synuclein-induced mice.
CONCLUSIONS
Therefore, our findings indicated that osmotin significantly rescued MPTP/α-synuclein-mediated PD neuropathology. Altogether, these results suggest that osmotin has potential neuroprotective effects in PD neuropathology and may provide opportunities to develop novel therapeutic interventions for the treatment of PD.
Topics: Humans; Mice; Animals; Parkinson Disease; alpha-Synuclein; Neuroprotective Agents; AMP-Activated Protein Kinases; Substantia Nigra; Signal Transduction; Dopaminergic Neurons; TOR Serine-Threonine Kinases; Mice, Inbred C57BL; Disease Models, Animal; Mammals
PubMed: 37568205
DOI: 10.1186/s12929-023-00961-z -
Aging Cell Oct 2023Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that...
Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.
Topics: Mice; Humans; Animals; Parkinson Disease; alpha-Synuclein; Dopaminergic Neurons; Disease Susceptibility; Stress, Psychological
PubMed: 37622525
DOI: 10.1111/acel.13970 -
Neuron Nov 2023Dopamine neurons of the ventral tegmental area (VTA) respond to food and social stimuli and contribute to both forms of motivation. However, it is unclear whether the...
Dopamine neurons of the ventral tegmental area (VTA) respond to food and social stimuli and contribute to both forms of motivation. However, it is unclear whether the same or different VTA neurons encode these different stimuli. To address this question, we performed two-photon calcium imaging in mice presented with food and conspecifics and found statistically significant overlap in the populations responsive to both stimuli. Both hunger and opposite-sex social experience further increased the proportion of neurons that respond to both stimuli, implying that increasing motivation for one stimulus increases overlap. In addition, single-nucleus RNA sequencing revealed significant co-expression of feeding- and social-hormone-related genes in individual VTA neurons. Taken together, our functional and transcriptional data suggest overlapping VTA populations underlie food and social motivation.
Topics: Mice; Animals; Dopaminergic Neurons; Ventral Tegmental Area; Food; Motivation
PubMed: 37657441
DOI: 10.1016/j.neuron.2023.08.003 -
Scientific Reports Sep 2023Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death pathway, while Parkinson's disease (PD) patients exhibit iron deposition and lipid peroxidation in...
Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death pathway, while Parkinson's disease (PD) patients exhibit iron deposition and lipid peroxidation in the brain. Thus, the features of ferroptosis highly overlap with the pathophysiological features of PD. Despite this superficial connection, the possible role(s) of ferroptosis-related (Fr) proteins in dopaminergic neurons and/or glial cells in the substantia nigra (SN) in PD have not been examined in depth. To explore the correlations between the different SN cell types and ferroptosis at the single-cell level in PD patients, and to explore genes that may affect the sensitivity of dopaminergic neurons to ferroptosis, we performed in silico analysis of a single cell RNA sequence (RNA-seq) set (GSE178265) from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in the different cell types in the human SN, and proceeded to perform enrichment analysis, constructing a protein-protein interaction network from the DEGs of dopaminergic neurons with the Metascape database. We examined the intersection of Fr genes present in the FerrDb database with DEGs from the GSE178265 set to identify Fr-DEGs in the different brain cells. Further, we identified Fr-DEGs encoding secreted proteins to implicate cell-cell interactions in the potential stimulation of ferroptosis in PD. The Fr-DEGs we identified were verified using the bulk RNA-seq sets (GSE49036 and GSE20164). The number of dopaminergic neurons decreased in the SN of PD patients. Interestingly, non-dopaminergic neurons possessed the fewest DEGs. Enrichment analysis of dopaminergic neurons' DEGs revealed changes in transmission across chemical synapses and ATP metabolic process in PD. The secreted Fr-DEGs identified were ceruloplasmin (CP), high mobility group box 1 (HMGB1) and transferrin (TF). The bulk RNA-seq set from the GEO database demonstrates that CP expression is increased in the PD brain. In conclusion, our results identify CP as a potential therapeutic target to protect dopaminergic neurons by reducing neurons' sensitivity to ferroptosis.
Topics: Humans; Ferroptosis; Parkinson Disease; Substantia Nigra; Ceruloplasmin; Dopaminergic Neurons; Hypesthesia; Iron
PubMed: 37717088
DOI: 10.1038/s41598-023-42574-4 -
Cells Feb 2024Parkinson's disease (PD) is a common movement disorder associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mutations in the... (Review)
Review
Parkinson's disease (PD) is a common movement disorder associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mutations in the PD-associated gene alter the structure and function of the encoded protein DJ-1, and the resulting autosomal recessively inherited disease increases the risk of developing PD. DJ-1 was first discovered in 1997 as an oncogene and was associated with early-onset PD in 2003. Mutations in DJ-1 account for approximately 1% of all recessively inherited early-onset PD occurrences, and the functions of the protein have been studied extensively. In healthy subjects, DJ-1 acts as an antioxidant and oxidative stress sensor in several neuroprotective mechanisms. It is also involved in mitochondrial homeostasis, regulation of apoptosis, chaperone-mediated autophagy (CMA), and dopamine homeostasis by regulating various signaling pathways, transcription factors, and molecular chaperone functions. While DJ-1 protects neurons against damaging reactive oxygen species, neurotoxins, and mutant α-synuclein, mutations in the protein may lead to inefficient neuroprotection and the progression of PD. As current therapies treat only the symptoms of PD, the development of therapies that directly inhibit oxidative stress-induced neuronal cell death is critical. DJ-1 has been proposed as a potential therapeutic target, while oxidized DJ-1 could operate as a biomarker for PD. In this paper, we review the role of DJ-1 in the pathogenesis of PD by highlighting some of its key neuroprotective functions and the consequences of its dysfunction.
Topics: Humans; Parkinson Disease; Oxidative Stress; Antioxidants; Dopaminergic Neurons; Protein Deglycase DJ-1
PubMed: 38391909
DOI: 10.3390/cells13040296 -
Neuron Feb 2024Ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) drive reward-related motivation. Although dopamine neurons are predominant, a substantial...
Ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) drive reward-related motivation. Although dopamine neurons are predominant, a substantial glutamatergic projection is also present, and a subset of these co-release both dopamine and glutamate. Optogenetic stimulation of VTA glutamate neurons not only supports self-stimulation but can also induce avoidance behavior, even in the same assay. Here, we parsed the selective contribution of glutamate or dopamine co-release from VTA glutamate neurons to reinforcement and avoidance. We expressed channelrhodopsin-2 (ChR2) in mouse VTA glutamate neurons in combination with CRISPR-Cas9 to disrupt either the gene encoding vesicular glutamate transporter 2 (VGLUT2) or tyrosine hydroxylase (Th). Selective disruption of VGLUT2 abolished optogenetic self-stimulation but left real-time place avoidance intact, whereas CRISPR-Cas9 deletion of Th preserved self-stimulation but abolished place avoidance. Our results demonstrate that glutamate release from VTA glutamate neurons is positively reinforcing but that dopamine release from VTA glutamate neurons can induce avoidance behavior.
Topics: Mice; Animals; Glutamic Acid; Dopamine; Reward; Ventral Tegmental Area; Dopaminergic Neurons; Vesicular Glutamate Transport Protein 2; Tyrosine 3-Monooxygenase
PubMed: 38086374
DOI: 10.1016/j.neuron.2023.11.002 -
International Journal of Molecular... Dec 2023Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread... (Review)
Review
Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which culminate in neuronal cell death. Importantly, αSyn pathology extends beyond neurons-it also encompasses spreading throughout the neuronal environment and internalization by microglia and astrocytes. Once internalized, glia can act as neuroprotective scavengers, which limit the spread of αSyn. However, they can also become reactive, thereby contributing to neuroinflammation and the progression of PD. Recent advances in αSyn research have enabled the molecular diagnosis of PD and accelerated the development of targeted therapies. Nevertheless, despite more than two decades of research, the cellular function, aggregation mechanisms, and induction of cellular damage by αSyn remain incompletely understood. Unraveling the interplay between αSyn, neurons, and glia may provide insights into disease initiation and progression, which may bring us closer to exploring new effective therapeutic strategies. Herein, we provide an overview of recent studies emphasizing the multifaceted nature of αSyn and its impact on both neuron and glial cell damage.
Topics: alpha-Synuclein; Dopaminergic Neurons; Neurodegenerative Diseases; Neuroglia; Parkinson Disease
PubMed: 38203531
DOI: 10.3390/ijms25010360 -
Experimental Neurology Dec 2023Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia... (Review)
Review
Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia circuits. Research over the past twenty-five years has identified that midbrain dopamine neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) co-release multiple other transmitters including glutamate and GABA, in addition to their canonical transmitter, dopamine. This review summarizes previous work characterizing neurotransmitter co-release from dopamine neurons, work examining potential changes in co-release dynamics that result in animal models of Parkinson's disease, and future opportunities for determining how dysfunction in co-release may contribute to circuit dysfunction in Parkinson's disease.
Topics: Animals; Parkinson Disease; Substantia Nigra; Ventral Tegmental Area; Synaptic Transmission; Dopaminergic Neurons; Neurotransmitter Agents
PubMed: 37802381
DOI: 10.1016/j.expneurol.2023.114562 -
Nature Communications Nov 2023Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one...
Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.
Topics: Humans; Parkinson Disease; Neural Stem Cells; Follow-Up Studies; Dopaminergic Neurons; Disease Progression
PubMed: 37996418
DOI: 10.1038/s41467-023-42862-7 -
Advanced Science (Weinheim,... Oct 2023The gene mutations of LRRK2, which encodes leucine-rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease...
The gene mutations of LRRK2, which encodes leucine-rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors investigate the effects of LRRK2 G2019S on endoplasmic reticulum (ER) stress in induced pluripotent stem cell (iPSC)-induced dopamine neurons and explore potential therapeutic targets in mice model. These findings demonstrate that LRRK2 G2019S significantly promotes ER stress in neurons and mice. Interestingly, inhibiting LRRK2 activity can ameliorate ER stress induced by the mutation. Moreover, LRRK2 mutation can induce ER stress by directly interacting with thrombospondin-1/transforming growth factor beta1 (THBS1/TGF-β1). Inhibition of LRRK2 kinase activity can effectively suppress ER stress and the expression of THBS1/TGF-β1. Knocking down THBS1 can rescue ER stress by interacting with TGF-β1 and behavior burden caused by the LRRK2 mutation, while suppression of TGF-β1 has a similar effect. Overall, it is demonstrated that the LRRK2 mutation promotes ER stress by directly interacting with THBS1/TGF-β1, leading to neural death in PD. These findings provide valuable insights into the pathogenesis of PD, highlighting potential diagnostic markers and therapeutic targets.
Topics: Animals; Mice; Dopaminergic Neurons; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Transforming Growth Factor beta1
PubMed: 37672887
DOI: 10.1002/advs.202303711