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Ageing Research Reviews Jun 2024Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by loss of dopaminergic neurons in the substantia nigra, as well as the... (Review)
Review
Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by loss of dopaminergic neurons in the substantia nigra, as well as the abnormal accumulation of misfolded α-synuclein. Clinically, PD is featured by typical motor symptoms and some non-motor symptoms. Up to now, although considerable progress has been made in understanding the pathogenesis of PD, there is still no effective therapeutic treatment for the disease. Thus, exploring new therapeutic strategies has been a topic that needs to be addressed urgently. Noteworthy, with the proposal of the microbiota-gut-brain axis theory, antimicrobial drugs have received significant attention due to their effects on regulating the intestinal microbiota. Nowadays, there is growing evidence showing that some antimicrobial drugs may be promising drugs for the treatment of PD. Data from pre-clinical and clinical studies have shown that some antimicrobial drugs may play neuroprotective roles in PD by modulating multiple biochemical and molecular pathways, including reducing α-synuclein aggregation, inhibiting neuroinflammation, regulating mitochondrial structure and function, as well as suppressing oxidative stress. In this paper, we summarized the effects of some antimicrobial drugs on PD treatment from recent pre-clinical and clinical studies. Then, we further discussed the potential of a few antimicrobial drugs for treating PD based on molecular docking and molecular dynamics simulation. Importantly, we highlighted the potential of clorobiocin as the therapeutic strategy for PD owing to its ability to inhibit α-synuclein aggregation. These results will help us to better understand the potential of antimicrobial drugs in treating PD and how antimicrobial drugs may alleviate or reverse the pathological symptoms of PD.
PubMed: 38942200
DOI: 10.1016/j.arr.2024.102387 -
Neurological Sciences : Official... Jun 2024Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS)...
Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.
PubMed: 38943019
DOI: 10.1007/s10072-024-07674-7 -
ELife Jun 2024Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these...
Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.
Topics: Animals; Dopaminergic Neurons; Serotonergic Neurons; Dorsal Raphe Nucleus; Mice; Disease Models, Animal; Oxidopamine; Parkinsonian Disorders; Male; Mice, Inbred C57BL; Desipramine; Norepinephrine
PubMed: 38940422
DOI: 10.7554/eLife.90278 -
Journal of Integrative Neuroscience May 2024Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain and the formation of intracellular protein aggregates known as Lewy bodies, of which a major component is the protein α-synuclein. Several studies have suggested that mitochondria play a central role in the pathogenesis of PD, encompassing both familial and sporadic forms of the disease. Mitochondrial dysfunction is attributed to bioenergetic impairment, increased oxidative stress, damage to mitochondrial DNA, and alteration in mitochondrial morphology. These alterations may contribute to improper functioning of the central nervous system and ultimately lead to neurodegeneration. The perturbation of mitochondrial function makes it a potential target, worthy of exploration for neuroprotective therapies and to improve mitochondrial health in PD. Thus, in the current review, we provide an update on mitochondria-based therapeutic approaches toward α-synucleinopathies in PD.
Topics: Humans; Parkinson Disease; Synucleinopathies; Mitochondria; Animals; alpha-Synuclein
PubMed: 38940084
DOI: 10.31083/j.jin2306109 -
Drug and Chemical Toxicology Jun 2024Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and...
Neuroprotective potential of solanesol against tramadol induced zebrafish model of Parkinson's disease: insights from neurobehavioral, molecular, and neurochemical evidence.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and subsequent depletion of dopamine in the striatum. Solanesol, an alcohol that acts as a precursor to coenzyme Q10, possesses potential applications in managing neurological disorders with antioxidant, anti-inflammatory, and neuromodulatory potential. In this study, a zebrafish model was employed to investigate the effects of solanesol in tramadol induced PD like symptoms. Zebrafish were administered tramadol injections (50 mg/kg) over a 20-day period. Solanesol was administered at doses of 25, 50, and 100 mg/kg, three hours prior to tramadol administration from day 11 to day 20. Behavioral tests assessing motor coordination were conducted on a weekly basis using open field and novel diving tank apparatus. On day 21, the zebrafish were euthanized, and brain tissues were examined for markers of oxidative stress, inflammation, and neurotransmitters level. Chronic tramadol treatment resulted in motor impairment, reduced antioxidant enzyme levels, enhanced release of proinflammatory cytokines in the striatum, and disrupted neurotransmitter balance. However, solanesol administration mitigated these effects and exhibited a neuroprotective effect against neurodegenerative alterations in the zebrafish model of PD. This was evident through improvements in behavior, modulation of biochemical markers, attenuation of neuroinflammation, restoration of neurotransmitters level, and enhancement of mitochondrial activity. The histopathological study also confirmed that solanesol dose dependently restored neuronal cell density which confirmed its neuroprotective potential. Further investigations are required to elucidate the underlying mechanisms of solanesol neuroprotective effects and evaluate its efficacy in human patients.
PubMed: 38938099
DOI: 10.1080/01480545.2024.2355542 -
Cell Reports. Medicine Jun 2024In rodents with unilateral ablation of neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA induces a progressive increase of...
In rodents with unilateral ablation of neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA induces a progressive increase of behavioral responses, a process known as behavioral sensitization. This sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of these mice, we find that the restoration of arrestin-3 fully rescues behavioral sensitization, whereas its mutant defective in c-Jun N-terminal kinase (JNK) activation does not. A 25-residue arrestin-3-derived peptide that facilitates JNK3 activation in cells, expressed ubiquitously or selectively in direct pathway striatal neurons, also fully rescues sensitization, whereas an inactive homologous arrestin-2-derived peptide does not. Behavioral rescue is accompanied by the restoration of JNK3 activity, as reflected by JNK-dependent phosphorylation of the transcription factor c-Jun in the dopamine-depleted striatum. Thus, arrestin-3-assisted JNK3 activation in direct pathway neurons is a critical element of the molecular mechanism underlying sensitization upon dopamine depletion and chronic L-DOPA treatment.
PubMed: 38936368
DOI: 10.1016/j.xcrm.2024.101623 -
International Journal of Computer... Jun 2024Parkinson disease (PD) is a common progressive neurodegenerative disorder in our ageing society. Early-stage PD biomarkers are desired for timely clinical intervention...
PURPOSE
Parkinson disease (PD) is a common progressive neurodegenerative disorder in our ageing society. Early-stage PD biomarkers are desired for timely clinical intervention and understanding of pathophysiology. Since one of the characteristics of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, we propose a feature extraction method for analysing the differences in the substantia nigra between PD and non-PD patients.
METHOD
We propose a feature-extraction method for volumetric images based on a rank-1 tensor decomposition. Furthermore, we apply a feature selection method that excludes common features between PD and non-PD. We collect neuromelanin images of 263 patients: 124 PD and 139 non-PD patients and divide them into training and testing datasets for experiments. We then experimentally evaluate the classification accuracy of the substantia nigra between PD and non-PD patients using the proposed feature extraction method and linear discriminant analysis.
RESULTS
The proposed method achieves a sensitivity of 0.72 and a specificity of 0.64 for our testing dataset of 66 non-PD and 42 PD patients. Furthermore, we visualise the important patterns in the substantia nigra by a linear combination of rank-1 tensors with selected features. The visualised patterns include the ventrolateral tier, where the severe loss of neurons can be observed in PD.
CONCLUSIONS
We develop a new feature-extraction method for the analysis of the substantia nigra towards PD diagnosis. In the experiments, even though the classification accuracy with the proposed feature extraction method and linear discriminant analysis is lower than that of expert physicians, the results suggest the potential of tensorial feature extraction.
PubMed: 38935246
DOI: 10.1007/s11548-024-03175-2 -
Behavioral Neuroscience Jun 2024A growing body of literature indicates that mediated learning techniques have specific utility for tapping into reality testing in animal models of neuropsychiatric...
A growing body of literature indicates that mediated learning techniques have specific utility for tapping into reality testing in animal models of neuropsychiatric illness. In particular, recent work has shown that animal models that recapitulate various endophenotypes of schizophrenia are particularly vulnerable to impairments in reality testing when undergoing mediated learning. Multiple studies have indicated that these effects are dopamine receptor 2-dependent and correlated with aberrant insular cortex (IC) activity. However, until now, the connection between dopamine and the IC had not been investigated. Here, we utilized a novel intersectional approach to label mesencephalic dopamine cells that specifically project to the insular cortex in both wild-type controls and transgenic mice expressing the dominant-negative form of the Disrupted-in-Schizophrenia-1 (DISC-1) gene. Using these techniques, we identified a population of cells that project from the ventral tegmental area (VTA) to the IC. Afterward, we conducted multiple studies to test the necessity of this circuit in behaviors ranging from gustatory detection to the maintenance of effort and, finally, mediated performance. Our results indicate that perturbations of the DISC-1 genetic locus lead to a reduction in the number of cells in the VTA → IC circuit. Behaviorally, VTA → IC circuitry does not influence gustatory detection or motivation to acquire sucrose reward; however, inactivation of this circuit differentially suppresses Pavlovian approach behavior in wild-type and DISC-1 transgenic mice during mediated performance testing. Moreover, under these testing conditions, inactivation of this circuit predisposes wild-type (but not DISC-1) mice to display impaired reality testing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Topics: Animals; Mice, Transgenic; Dopaminergic Neurons; Mice; Insular Cortex; Male; Ventral Tegmental Area; Mice, Inbred C57BL; Neural Pathways; Reward; Disease Models, Animal; Dopamine; Nerve Tissue Proteins; Mesencephalon; Schizophrenia
PubMed: 38934920
DOI: 10.1037/bne0000580 -
Frontiers in Neuroscience 2024Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the...
BACKGROUND
Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the progression of PD. It was proposed that neuroinflammation leads to neuronal death, making targeting neuroinflammation a promising therapeutic strategy. Our previous studies have demonstrated that rhein protects neurons by inhibiting neuroinflammation, and it has been found to exhibit neuroprotective effects in Alzheimer's disease and epilepsy, but its neuroprotective mechanisms and effects on PD are still unclear.
METHODS
PD animal model was induced by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). ELISA, RT-qPCR, western blot and Immunofluorescence were used to detect the levels of inflammatory cytokines and M1 polarization markers. The protein expression levels of signaling pathways were measured by western blot. Hematoxylin-eosin (HE) staining showed that rhein did not damage the liver and kidney. Two behavioral tests, pole test and rotarod test, were used to evaluate the improvement effect of rhein on movement disorders. The number of neurons in the substantia nigra was evaluated by Nissl staining. Immunohistochemistry and western blot were used to detect tyrosine hydroxylase (TH) and α-synuclein.
RESULTS
Rhein inhibited the activation of MAPK/IκB signaling pathway and reduced the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and M1 polarization markers of microglia . In a mouse model of PD, rhein ameliorated movement disorders, reduced dopaminergic neuron damage and α-synuclein deposition.
CONCLUSION
Rhein inhibits neuroinflammation through MAPK/IκB signaling pathway, thereby reducing neurodegeneration, α-synuclein deposition, and improving movement disorders in Parkinson's disease.
PubMed: 38933815
DOI: 10.3389/fnins.2024.1396345 -
Life (Basel, Switzerland) Jun 2024Parkinson's disease (PD) caused by gene triplication (3X) leads to early onset, rapid progression, and often dementia. Understanding the impact of 3X and its absence is...
Parkinson's disease (PD) caused by gene triplication (3X) leads to early onset, rapid progression, and often dementia. Understanding the impact of 3X and its absence is crucial. This study investigates the differentiation of human induced pluripotent stem cell (hiPSC)-derived floor-plate progenitors into dopaminergic neurons. Three different genotypes were evaluated in this study: patient-derived hiPSCs with 3X, a gene-edited isogenic line with a frame-shift mutation on all alleles ( 4KO), and a normal wild-type control. Our aim was to assess how the substantia nigra pars compacta (SNpc) microenvironment, damaged by 6-hydroxydopamine (6-OHDA), influences tyrosine hydroxylase-positive (Th+) neuron differentiation in these genetic variations. This study confirms successful in vitro differentiation into neuronal lineage in all cell lines. However, the 4KO line showed unusual LIM homeobox transcription factor 1 alpha (Lmx1a) extranuclear distribution. Crucially, both 3X and 4KO lines had reduced Th+ neuron expression, despite initial successful neuronal differentiation after two months post-transplantation. This indicates that while the SNpc environment supports early neuronal survival, gene alterations-either amplification or knock-out-negatively impact Th+ dopaminergic neuron maturation. These findings highlight 's critical role in PD and underscore the value of hiPSC models in studying neurodegenerative diseases.
PubMed: 38929711
DOI: 10.3390/life14060728