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Cell Death & Disease Jun 2024The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson's disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is...
The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson's disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. L-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.
Topics: Dopaminergic Neurons; Animals; Amidohydrolases; Mitochondria; Parkinson Disease; Arginine; Endoplasmic Reticulum; Rats; Nitric Oxide; Male; Rats, Sprague-Dawley; Humans; GTP Phosphohydrolases; Rotenone; Mitochondrial Proteins; Mitochondria Associated Membranes
PubMed: 38849335
DOI: 10.1038/s41419-024-06772-w -
ACS Chemical Neuroscience Jun 2024Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (DR) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate DR antagonists. However, developing selective DR antagonists suitable for clinical translation remains a challenge.
Topics: Quantitative Structure-Activity Relationship; Humans; Computer-Aided Design; Receptors, Dopamine D4; Spiro Compounds; Dopamine Antagonists; Neural Networks, Computer; Parkinson Disease; Animals; Drug Design
PubMed: 38847395
DOI: 10.1021/acschemneuro.4c00086 -
Neural Regeneration Research Jun 2024The globus pallidus plays a pivotal role In the basal ganglia circuit. Parkinson's disease Is characterized by degeneration of dopamine-producing cells in the substantia...
The globus pallidus plays a pivotal role In the basal ganglia circuit. Parkinson's disease Is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore, bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico-striato-pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease, particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia-thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity, and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.
PubMed: 38845220
DOI: 10.4103/NRR.NRR-D-23-01660 -
Frontiers in Cellular Neuroscience 2024Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During...
Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During myelination, synaptic vesicle release from axons promotes sheath stabilization and growth on a subset of neuron subtypes. In comparison, it is unknown if pre-myelinating oligodendrocyte process extensions selectively interact with specific neural circuits or axon subtypes, and whether the formation and stabilization of these neuron-glia interactions involves synaptic vesicle release. In this study, we used fluorescent reporters in the larval zebrafish model to track pre-myelinating oligodendrocyte process extensions interacting with spinal axons utilizing imaging. Monitoring motile oligodendrocyte processes and their interactions with individually labeled axons revealed that synaptic vesicle release regulates the behavior of subsets of process extensions. Specifically, blocking synaptic vesicle release decreased the longevity of oligodendrocyte process extensions interacting with reticulospinal axons. Furthermore, blocking synaptic vesicle release increased the frequency that new interactions formed and retracted. In contrast, tracking the movements of all process extensions of singly-labeled oligodendrocytes revealed that synaptic vesicle release does not regulate overall process motility or exploratory behavior. Blocking synaptic vesicle release influenced the density of oligodendrocyte process extensions interacting with reticulospinal and serotonergic axons, but not commissural interneuron or dopaminergic axons. Taken together, these data indicate that alterations to synaptic vesicle release cause changes to oligodendrocyte-axon interactions that are neuron subtype specific.
PubMed: 38841202
DOI: 10.3389/fncel.2024.1386352 -
Nature Jun 2024All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders. Another recently appreciated...
All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
Topics: Ventral Tegmental Area; Animals; Reward; Dopaminergic Neurons; Mice; Myelin Sheath; Morphine; Male; Nucleus Accumbens; Neuronal Plasticity; Oligodendroglia; GABAergic Neurons; Optogenetics; Analgesics, Opioid; Dopamine; Female; Mice, Inbred C57BL
PubMed: 38839962
DOI: 10.1038/s41586-024-07525-7 -
Nature Communications Jun 2024Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent...
Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.
Topics: Animals; Deep Brain Stimulation; Mice; Hippocampus; Ultrasonic Waves; Mice, Inbred C57BL; Dopaminergic Neurons; Male; Dopamine; Proto-Oncogene Proteins c-fos; Substantia Nigra; Neurons; Transducers
PubMed: 38834558
DOI: 10.1038/s41467-024-48748-6 -
Neuroscience Insights 2024Our minds impact motor outputs. Such mind-motor interactions are critical for understanding motor control mechanisms and optimizing motor performance. In particular,...
Our minds impact motor outputs. Such mind-motor interactions are critical for understanding motor control mechanisms and optimizing motor performance. In particular, incentive motivation strongly enhances motor performance. Dopaminergic neurons located in the ventral midbrain (VM) are believed to be the center of incentive motivation. Direct projections from the VM to the primary motor cortex constitute a mesocortical pathway. However, the functional role of this pathway in humans remains unclear. Recently, we demonstrated the functional role of the mesocortical pathway in human motor control in the context of incentive motivation by using functional magnetic resonance imaging (fMRI). Incentive motivation remarkably improved not only reaction times but also the peak grip force in subsequent grip responses. Although the reaction time has been used as a proxy for incentive motivation mediated by dopaminergic midbrain activity, the premovement activity of the mesocortical pathway is involved in controlling the force strength rather than the initiation of subsequent force generation. In this commentary, we review our recent findings and discuss remaining questions regarding the functional role of the mesocortical pathway in mind-motor interactions.
PubMed: 38827248
DOI: 10.1177/26331055241256948 -
Experimental & Molecular Medicine Jun 2024The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for...
The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.
PubMed: 38825641
DOI: 10.1038/s12276-024-01242-x -
Brain Research Bulletin Aug 2024Parkinson's disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis....
Parkinson's disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16 S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16 S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.
Topics: Animals; Dopaminergic Neurons; Intercellular Adhesion Molecule-1; Mice; Male; Mice, Inbred C57BL; Disease Models, Animal; Neuroinflammatory Diseases; Gastrointestinal Microbiome; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Inflammation; Substantia Nigra; Microglia; Astrocytes; Parkinsonian Disorders; MPTP Poisoning
PubMed: 38825252
DOI: 10.1016/j.brainresbull.2024.110989 -
Nature Communications May 2024Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β...
Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.
Topics: alpha-Synuclein; Lymphocyte Activation Gene 3 Protein; Humans; Animals; Mice; Antigens, CD; Dopaminergic Neurons; Parkinson Disease; Protein Binding; Amyloid beta-Protein Precursor; Mice, Knockout; Male; Mice, Inbred C57BL; Female
PubMed: 38821932
DOI: 10.1038/s41467-024-49016-3