Nigrostriatal Dopaminergic Pathway Research Articles

DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson’s disease

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.

Midbrain dopaminergic degeneration differentially modulates primary motor cortex activity and motor behavior in hemi-parkinsonian rats.

Parkinson's disease (PD) is marked by degeneration in the nigrostriatal dopaminergic pathway, affecting motor control via complex changes in the cortico-basal ganglia-thalamic motor network, including the primary motor cortex (M1). The modulation of M1 neuronal activity by dopaminergic inputs, particularly from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), plays a crucial role in PD pathophysiology. This study investigates how nigrostriatal dopaminergic degeneration influences M1 neuronal activity in rats using in vivo calcium imaging. Histological analysis confirmed dopaminergic lesion severity, with high lesion level rats showing significant motor deficits. Levodopa treatment improved fine motor abilities, particularly in high lesion level rats. Analysis of M1 calcium signals based on dopaminergic lesion severity revealed distinct M1 activity patterns. Animals with low dopaminergic lesion showed increased calcium events, while high lesion level rats exhibited decreased activity, partially restored by levodopa. These findings suggest that M1 activity is more sensitive to transient fluctuations in dopaminergic transmission, rather than to chronic high or low dopaminergic signaling. This study underscores the complex interplay between dopaminergic signaling and M1 neuronal activity in PD symptoms development. Further research integrating behavioral and calcium imaging data can elucidate mechanisms underlying motor deficits and therapeutic responses in PD.

Impact of alogliptin on lipopolysaccharide-induced experimental Parkinson's disease: Unrevealing neurochemical and histopathological alterations in rodents.

BackgroundDegeneration of the nigrostriatal dopaminergic pathway has been seen as a significant cause of movement disability in Parkinson's disease (PD) patients. However, the exact reason for these degenerative changes has remained obscure. In recent years, incretins have been neuroprotective in various pathologies. In the current study, we have investigated the neuroprotective potential of alogliptin (Alo), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, in a lipopolysaccharide (LPS) induced experimental model of PD. Experimental approachLPS (5μg/5 μl) was infused intranigrally to induce PD in experimental rats. Post-LPS infusion, these animals were treated with Alo for 21 days in three successive dosages of 10, 20, and 40 mg/kg/day/per oral. The study is well supported with the determinations of motor functions biochemical, neurochemical, and histological analysis. Key resultsIntranigral infusion of LPS in rats produced motor deficit. It was accompanied by oxidative stress, elevation in neuroinflammatory cytokines, altered neurochemistry, and degenerative changes in the striatal brain region. While Alo abrogated LPS-induced biochemical/neurochemical alterations, improved motor functions, and preserved neuronal morphology in LPS-infused rats. ConclusionThe observed neuroprotective potential of Alo may be due to its antioxidant and anti-inflammatory actions and its ability to modulate monoaminergic signals. Nonetheless, current findings suggest that improving the availability of incretins through DPP-IV inhibition is a promising strategy for treating Parkinson's disease.

Aqueous extract of Swietenia macrophylla leaf exerts an anti-inflammatory effect in a murine model of Parkinson's disease induced by 6-OHDA.

Parkinson's disease affects 2% of the population aged over 65 years and is the second most common neurodegenerative disorder in the general population. The appearance of motor symptoms is associated with the degeneration of dopaminergic neurons in the nigrostriatal pathway. Clinically significant nonmotor symptoms are also important for severe disability with disease progression. Pharmacological treatment with levodopa, which involves dopamine restitution, results in a temporary improvement in motor symptoms. Among the mechanisms underlying the pathogenesis of the disease are exacerbated oxidative stress, mitochondrial dysfunction, and neuroinflammation. A phytochemical prospecting study showed that the aqueous extract of the leaves from Swietenia macrophylla (Melineaceae), known as mahogany, has polyphenols with antioxidant and anti-inflammatory capacity in a significantly higher percentage than leaf extracts from other Amazonian plants. Furthermore, the antioxidant and anti-inflammatory capacity of aqueous extract of mahogany leaf has already been demonstrated in an in vitro model. In this study, we hypothesized that the aqueous extract of mahogany leaf (AEML) has a neuroprotective effect in a murine model of Parkinson's disease induced by 6-hydroxidopamine (6-OHDA), due to antioxidant and anti-inflammatory properties of its phenolic compounds. Mice were treated daily with the mahogany extract at a dose of 50 mg/kg, starting 7 days before 6-OHDA infusion until post-surgery day 7. The animals from the 6-OHDA/mahogany group, which corresponds to animals injected with the toxin and treated with aqueous extract of the mahogany leaf, presented distinct behavioral phenotypes after apomorphine challenge and were therefore subdivided into 2 groups, 6-OHDA/mahogany F1 and 6-OHDA/mahogany F2. The F1 group showed a significant increase in contralateral rotations, whereas the F2 group did not show rotations after the apomorphine stimulus. In the F1 group, there was an increase, although not significant, in motor performance in the open field and elevated plus maze tests, whereas in the F2 group, there was significant improvement, which may be related to the lesser degree of injury to the nigrostriatal dopaminergic pathway. The TH+ histopathological analysis, a dopaminergic neuron marker, confirmed that the lesion to the nigrostriatal dopaminergic pathway was more pronounced in 6-OHDA/mahogany F1 than in 6-OHDA/mahogany F2. Our main result consisted of signs of improvement in the inflammatory profile in both the F1 and F2 6-OHDA/mahogany groups, such as a lower number of IBA-1+ microglial cells in the ventral striatum and substantia nigra pars compacta and a reduction in GFAP+ expression, an astrocyte marker, in the dorsal striatum. In this study, several bioactive compounds in the aqueous extract of mahogany leaf may have contributed to the observed beneficial effects. Further studies are necessary to better characterize their applicability for treating chronic degenerative diseases with inflammatory and oxidative bases, such as Parkinson's disease.

Dopamine activity in the nigrostriatal pathway alters cue-induced risky choice patterns in female rats.

Deficits in cost/benefit decision making is a critical risk factor for gambling disorder. Reward-paired cues may play an important role, as these stimuli can enhance risk preference in rats. Despite extensive research implicating the dorsal striatum in the compulsive aspects of addiction, the role of nigrostriatal dopaminergic activity in cue-induced risk preference remains unclear, particularly in females. Accordingly, we examined the effects of manipulating the dopaminergic nigrostriatal pathway on cue-induced risky choice in female rats. TH:Cre rats were trained on the cued version of the rat Gambling Task. This task was designed such that maximal reward is attained by avoiding the high-risk, high-reward options and instead favouring the options associated with lower per-trial gains, as they feature less frequent and shorter time-out penalties. Adding reward-paired audiovisual cues to the task leads to greater risky choice on average. To assess the role of the nigrostriatal pathway, a viral vector carrying either Cre-dependent inhibitory or excitatory DREADD was infused into the substantia nigra. Rats then received clozapine-N-oxide either during task acquisition or after a stable performance baseline was reached. Inhibition of this pathway accelerated the development of risk preference in early sessions and increased risky choice during performance, but long-term inhibition actually improved decision making. Activation of this pathway had minimal effects. These results provide evidence for the involvement of the dopaminergic nigrostriatal pathway in cue-induced risk preference in females, therefore shedding light on its role in cost/benefit decision-making deficits and expanding our knowledge of the female dopaminergic system.

Practical Overview of 123I-Ioflupane Imaging in Parkinsonian Syndromes.

Parkinsonian syndromes are a heterogeneous group of progressive neurodegenerative disorders involving the nigrostriatal dopaminergic pathway and are characterized by a wide spectrum of motor and nonmotor symptoms. These syndromes are quite common and can profoundly impact the lives of patients and their families. In addition to classic Parkinson disease, parkinsonian syndromes include multiple additional disorders known collectively as Parkinson-plus syndromes or atypical parkinsonism. These are characterized by the classic parkinsonian motor symptoms with additional distinguishing clinical features. Dopamine transporter SPECT has been developed as a diagnostic tool to assess the levels of dopamine transporters in the striatum. This imaging assessment, which uses iodine 123 (123I) ioflupane, can be useful to differentiate parkinsonian syndromes caused by nigrostriatal degeneration from other clinical mimics such as essential tremor or psychogenic tremor. Dopamine transporter imaging plays a crucial role in diagnosing parkinsonian syndromes, particularly in patients who do not clearly fulfill the clinical criteria for diagnosis. Diagnostic clarification can allow early treatment in appropriate patients and avoid misdiagnosis. At present, only the qualitative interpretation of dopamine transporter SPECT is approved by the U.S. Food and Drug Administration, but quantitative interpretation is often used to supplement qualitative interpretation. The authors provide an overview of patient preparation, common imaging findings, and potential pitfalls that radiologists and nuclear medicine physicians should know when performing and interpreting dopamine transporter examinations. Alternatives to 123I-ioflupane imaging for the evaluation of nigrostriatal degeneration are also briefly discussed. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Intenzo and Colarossi in this issue.

Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson's disease

Parkinson's disease, a progressive neurodegenerative disorder, involves gradual degeneration of the nigrostriatal dopaminergic pathway, leading to neuronal loss within the substantia nigra pars compacta and dopamine depletion. Molecular factors, including neuroinflammation, impaired protein homeostasis, and mitochondrial dysfunction, contribute to the neuronal loss. Deep brain stimulation, a form of neuromodulation, applies electric current through stereotactically implanted electrodes, effectively managing motor symptoms in advanced Parkinson's disease patients. Deep brain stimulation exerts intricate effects on neuronal systems, encompassing alterations in neurotransmitter dynamics, microenvironment restoration, neurogenesis, synaptogenesis, and neuroprotection. Contrary to initial concerns, deep brain stimulation demonstrates antiinflammatory effects, influencing cytokine release, glial activation, and neuronal survival.This review investigates the intricacies of deep brain stimulation mechanisms, including insertional effects, histological changes, and glial responses, and sheds light on the complex interplay between electrodes, stimulation, and the brain. This exploration delves into understanding the role of neuroinflammatory pathways and the effects of deep brain stimulation in the context of Parkinson's disease, providing insights into its neuroprotective capabilities.

Study of non-motor Symptoms in Parkinsons disease and its impact on their quality of life

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the degeneration of dopaminergic nigrostriatal pathway. Its incidence ranges from 1 to 2 per 1000 in general population. Its a complex disorder characterised by motor and non-motor symptoms that can impair the quality of life (QoL). In the presence of effective symptomatic therapies for the motor symptoms of Parkinson's disease, the non-motor symptoms have become the major prognostic factors determining the overall disease burden and everyday function in Parkinson’s disease patients. Our study aimed at assessing the frequency and proportion of non-motor symptoms in PD patients and to assess their impact on QoL. A total of 88 PD patients visiting the outpatient department of Neurology at Goa Medical College were assessed for various non-motor symptoms using a semi – structured questionnaire and appropriate scales. Quality of life was assessed using PDQ-39 questionnaire. Patients satisfying the United Kingdom Parkinson’s Disease brain bank criteria for idiopathic Parkinson’s diseases were included in the study Single centre, Cross-sectional study. Mean age of study population was 68 years and mean duration of the disease was 5yrs. Attention and memory were the most frequently reported domain in the study population (52 patients, 59.75 percent) followed by mood and cognition (46 patients, 52.74 percent). The least reported symptom was perceptual problems including delusions and hallucinations (11.74%) and miscellaneous domain (10.93 percent) which included pain, olfactory dysfunction, increased perspiration and weight fluctuations. The mean UPDRS (part 3) score was found to be 33.24± 17.37 with values ranging from 3.57 (mild motor impairment) to 44.64 (severe motor impairment).The QoL assessment showed that impairment of Mobility had a major impact on QoL followed by activities of daily living and emotional well-being. Correlation between Non-motor symptoms and PDQ-39 revealed that mood, cognition and perceptual problems had an adverse outcome on their emotional well-being and deficit in attention and memory had significant outcomes on communication. This study highlights the fact that non-motor symptoms in PD significantly impair quality of life and we should incorporate screening tools to evaluate patients with autonomic, sensory or mood disturbances so that they are detected at the earliest as most of them precede motor symptoms by decades.

Unraveling the role of glial cell line-derived neurotrophic factor in the treatment of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative condition with its prevalence projected to 8.9 million individuals globally in the year 2019. Parkinson's disease affects both motor and certain non-motor functions of an individual. Numerous research has focused on the neuroprotective effect of the glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease. Discovered in 1993, GDNF is a neurotrophic factor identified from the glial cells which was found to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. Given this property, recent studies have focused on the exogenous administration of GDNF for relieving Parkinson's disease-related symptoms both at a pre-clinical and a clinical level. This review will focus on enumerating the molecular connection between Parkinson's disease and GDNF and shed light on all the available drug delivery approaches to facilitate the selective delivery of GDNF into the brain paving the way as a potential therapeutic candidate for Parkinson's disease in the future.

The interplay between neuroinflammatory pathways and Parkinson's disease

Parkinson's disease, a progressive neurodegenerative disorder predominantly affecting elderly, is marked by the gradual degeneration of the nigrostriatal dopaminergic pathway, culminating in neuronal loss within the substantia nigra pars compacta (SNpc) and dopamine depletion. At the molecular level, neuronal loss in the SNpc has been attributed to factors including neuroinflammation, impaired protein homeostasis, as well as mitochondrial dysfunction and the resulting oxidative stress. This review focuses on the interplay between neuroinflammatory pathways and Parkinson's disease, drawing insights from current literature.

27-Hydroxycholesterol Drives the Spread of α-Synuclein Pathology in Parkinson's Disease.

The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27-OHC plays a role in α-Syn aggregation and propagation remains elusive. The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation. Purified recombinant α-Syn, neuronal cultures, and α-Syn fibril-injected mouse model of PD were treated with 27-OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27-OHC on α-Syn pathology in vivo. 27-OHC accelerates the aggregation of α-Syn and enhances the seeding activity of α-Syn fibrils. Furthermore, the 27-OHC-modified α-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified α-Syn fibrils induces enhanced spread of α-Syn pathology and dopaminergic neurodegeneration compared with pure α-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of α-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic α-Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27-OHC plays an important role in the pathogenesis of PD. 27-OHC promotes the aggregation and spread of α-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a disease-modifying therapy to halt the progression of α-Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.

Research progress on gas signal molecular therapy for Parkinson's disease.

The pathogenesis of Parkinson's disease (PD) remains unclear. Among the pathological manifestations is the progressive degeneration of the nigrostriatal dopaminergic pathway, leading to massive loss of neurons in the substantia nigra pars compacta and dopamine (DA) depletion. Therefore, the current drug treatment is primarily based on DA supplementation and delaying the progression of the disease. However, as patients' symptoms continue to worsen, the drug effect will gradually decrease or even disappear, thereby further aggravating clinical symptoms. Gas signaling molecules, such as hydrogen sulfide (H2S), nitric oxide (NO), carbon monoxide (CO), and hydrogen (H2), exhibit pleiotropic biological functions and play crucial roles in physiological and pathological effects. In common neurodegenerative diseases including Alzheimer's disease and PD, gas signal molecules can prevent or delay disease occurrence via the primary mechanisms of antioxidation, anti-inflammatory response, and antiapoptosis. This article reviews the therapeutic progress of gas signaling molecules in PD models and discusses the possibility of their clinical applications.

Short-term hindlimb unloading negatively affects dopaminergic transmission in the nigrostriatal system of mice.

The nigrostriatal system composed of the dorsal striatum and the substantia nigra (SN) is highly involved in the control of motor behavior. Various extremal and pathological conditions as well as social isolation (SI) may cause an impairment of locomotor function; however, corresponding alterations in the nigrostriatal dopaminergic pathway are far from full understanding. Here, we analyzed the effect of 3-day hindlimb unloading (HU) and SI on the key players of dopamine transmission in the nigrostriatal system of CD1 mice. Three groups of mice were analyzed: group-housed (GH), SI, and HU animals. Our data showed a significant decrease in the expression and phosphorylation of tyrosine hydroxylase (TH) in the SN and dorsal striatum of HU mice that suggested attenuation of dopamine synthesis in response to HU. In the dorsal striatum of HU mice, the downregulation of TH expression was also observed indicating the effect of unloading; however, TH phosphorylation at Ser40 was mainly affected by SI pointing on an impact of isolation too. Expression of dopamine receptors D1 in the dorsal striatum of HU mice was increased suggesting a compensatory response, but the activity of downstream signaling pathways involving protein kinase A and cAMP response element-binding protein was inhibited. At the same time, SI alone did not affect expression of DA receptors and activity of downstream signaling in the dorsal striatum. Obtained data let us to conclude that HU was the main factor which impaired dopamine transmission in the nigrostriatal system but SI made some contribution to its negative effects.

Hemisphere-specific characterization of projections from the Pedunculopontine Tegmental Nucleus to Substantia Nigra pars Compacta dopaminergic neurons

The neurotransmitter dopamine has been shown to be implicated in motivation and reward, notably in the nigrostriatal dopaminergic pathway. Within this pathway, our research focuses on the synapse between the midbrain regions pedunculopontine tegmental nucleus (PPN) and substantia nigra pars compacta (SNc). The PPN is unusual in that it sends projections to both ipsilateral and contralateral sides of the brain, unlike other brain structures that confine their innervations to either ipsilateral or contralateral. To understand the nature of these inputs, the current study focuses specifically on the glutamatergic excitatory projections as well as the GABAergic inhibitory projections within the PPN-SNc circuit using optogenetics in combination with electrophysiological and confocal microscopic methods. These projections have not been previously studied due to a lack of tools. The goal of this particular study is to investigate how hemisphere-specific inputs differ in their synaptic strength. Stereotaxic surgery is performed to unilaterally deliver virus that encodes expression for a depolarizing light-gated ion channel, Channelrhodopsin (ChR2), tagged with yellow fluorescent protein. Light-gated channels were activated to selectively depolarize PPN axons located in the input region that subsequently stimulates synapses onto dopamine neurons. Electrophysiological tests were then run to obtain electrical recordings that permit the quantification of excitatory and inhibitory responses within the PPN-SNc pathway. Finally, brain slices were immunostained with antibodies to tyrosine hydroxylase, a precursor to dopamine, glutamic acid decarboxylase, a GABA-synthesizing enzyme, and vesicular glutamate transporter to visualize dopaminergic neurons, GABAergic projections, and glutamatergic projections, respectively. Confocal images were collected in order to quantify the macroscopic distribution of ipsilateral and contralateral projections in the SNc. We are also using injections of retrograde beads into the SNc to label projecting neurons in the PPN to confirm the hemisphere specificity seen in anterograde labeling.Preliminary findings suggest GABAergic PPN efferents project only to ipsilateral SNc. However, glutamatergic PPN efferent project to both ipsilateral and contralateral SNc, with differing strengths. Our research will permit greater clarity for future studies which seek to understand the underlying neural network and synaptic-level processes of the nigrostriatal dopaminergic pathway. Acknowledgements: This research was supported by: Murchison Summer Research Fellowship, Biology Summer Research Fellowship, Trinity University Start-Up Funds, McNair Scholars Program, the Brain and Behavior Research Foundation NARSAD Young Investigator Award, and the Mary E. Groff Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Protection and Repair of the Nigrostriatal Pathway with Stem-Cell-Derived Carotid Body Glomus Cell Transplants in Chronic MPTP Parkinsonian Model.

Antiparkinsonian carotid body (CB) cell therapy has been proven to be effective in rodent and nonhuman primate models of Parkinson's disease (PD), exerting trophic protection and restoration of the dopaminergic nigrostriatal pathway. These neurotrophic actions are mediated through the release of high levels of glial-cell-line-derived neurotrophic factor (GDNF) by the CB transplant. Pilot clinical trials have also shown that CB autotransplantation can improve motor symptoms in PD patients, although its effectiveness is affected by the scarcity of the grafted tissue. Here, we analyzed the antiparkinsonian efficacy of in vitro-expanded CB dopaminergic glomus cells. Intrastriatal xenografts of rat CB neurospheres were shown to protect nigral neurons from degeneration in a chronic MPTP mouse PD model. In addition, grafts performed at the end of the neurotoxic treatment resulted in the repair of striatal dopaminergic terminals through axonal sprouting. Interestingly, both neuroprotective and reparative effects induced by in vitro-expanded CB cells were similar to those previously reported by the use of CB transplants. This action could be explained because stem-cell-derived CB neurospheres produce similar amounts of GDNF compared to native CB tissue. This study provides the first evidence that in vitro-expanded CB cells could be a clinical option for cell therapy in PD.

Parkinsonism after ventriculoperitoneal shunt for hydrocephalus

BackgroundParkinsonism after ventriculoperitoneal shunt in patients with hydrocephalus is a rare and profound complication that is often misdiagnosed, causing treatment to be delayed. To date, the characteristics of this disease have not been well described and summarized. Here, we report a rare case of parkinsonism after ventriculoperitoneal shunt; symptoms were aggravated by antipsychotic drugs but showed a good response to Madopar. Such cases have rarely been reported previously.Case presentationA 44-year-old man presented with parkinsonism, bilateral pyramidal tract signs, and oculomotor impairment four years after a successful ventriculoperitoneal shunt for idiopathic aqueduct stenosis resulting in obstructive hydrocephalus. Brain magnetic resonance imaging and computed tomography showed fluctuations in the lateral ventricle and the third ventricle without any intervention. The patient’s condition was aggravated by antipsychotic drugs but showed a good response to Madopar.ConclusionThis observation suggests that parkinsonism in this patient was caused by reversible dysfunction of the presynaptic nigrostriatal dopaminergic pathway due to fluctuations in the lateral ventricle, representing the first hit to the dopaminergic signalling pathway, and antipsychotic drugs had an antagonistic effect on dopamine D2 receptors, representing the second hit. In addition, we summarize the pathophysiological mechanisms, clinical manifestations, treatments, and prognoses of this complication in 38 patients who met the inclusion criteria in 24 previous studies to increase neurologists’ understanding of the disease.

Synapsin III Regulates Dopaminergic Neuron Development in Vertebrates.

Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. Polymorphisms in the Synapsin III (Syn III) gene can associate with ADHD onset and even affect the therapeutic response to the gold standard ADHD medication, methylphenidate (MPH), a monoamine transporter inhibitor whose efficacy appears related with the stimulation of brain-derived neurotrophic factor (BDNF). Interestingly, we previously showed that MPH can bind Syn III, which can regulate neuronal development. These observations suggest that Syn III polymorphism may impinge on ADHD onset and response to therapy by affecting BDNF-dependent dopaminergic neuron development. Here, by studying zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and human induced pluripotent stem cells (iPSCs)-derived neurons subjected to Syn III RNA interference, we found that Syn III governs the earliest stages of dopaminergic neurons development and that this function is conserved in vertebrates. We also observed that in mammals Syn III exerts this function acting upstream of brain-derived neurotrophic factor (BDNF)- and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. Collectively, these findings own significant implications for deciphering the biological basis of ADHD.

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease (PD). However, the mechanisms underlying this association remain unclear. In the present study, we found that high glucose (HG) levels in the cerebrospinal fluid (CSF) of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine (6-OHDA) on the development of motor disorders, and the damage to the nigrostriatal dopaminergic neuronal pathway. In vitro, HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor (NGF) (NGF-PC12). Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle (TCA cycle) activity, which was closely related to abnormal mitochondrial fusion, thus resulting in mitochondrial loss. Interestingly, HG-induced upregulation of pyruvate kinase M2 (PKM2) combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells. In addition, we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA. Furthermore, we found that shikonin (SK), an inhibitor of PKM2, restored the mitochondrial number, promoted TCA cycle activity, reversed hyperglycolysis, enhanced the tolerance of cultured neurons to 6-OHDA, and reduced the risk of PD in diabetic rats. Overall, our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2, leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA. Thus, the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

The impact on speech with different deep brain stimulation settings in Parkinson's disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway which affects movement initiation and maintenance, causing hypokinetic dysarthria in PD. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been widely used to manage rigidity, bradykinesias and drug-induced dyskinesias. While STN DBS successfully manages many symptoms of PD, speech response has been widely reported as “no or negative impact”. The High-Frequency Setting (HFS) is more focused within the STN which is known to control appendicular symptoms. However, the unintentional HFS current spreading to adjacent brain areas, such as the corticospinal and corticobulbar tracts, was thought to contribute to the deterioration of axial symptoms, including speech. The Low-Frequency Setting (LFS) extends more dorsally and ventrally towards surrounding structures, hence does not show the same negative impact and may reduce the negative impact on the axial functions including speech. This double-blind, randomized perception study assesses the impact of two deep brain stimulation (DBS) settings (high-frequency stimulation and interleave-interlink dual-frequency paradigm) on speech produced by 20 patients with PD. The impact of the two testing conditions was different for different Syllable Types with significant negative correlation between the articulatory rate and articulatory accuracy.

Adaptive structural changes in the motor cortex and white matter in Parkinson’s disease

Parkinson’s disease (PD) is a movement disorder characterized by the early loss of nigrostriatal dopaminergic pathways producing significant network changes impacting motor coordination. Recently three motor stages of PD have been proposed (a silent period when nigrostriatal loss begins, a prodromal motor period with subtle focal manifestations, and clinical PD) with evidence that motor cortex abnormalities occur to produce clinical PD[8]. We directly assess structural changes in the primary motor cortex and corticospinal tract using parallel analyses of longitudinal clinical and cross-sectional pathological cohorts thought to represent different stages of PD. 18F-FP-CIT positron emission tomography and subtle motor features identified patients with idiopathic rapid-eye-movement sleep behaviour disorder (n = 8) that developed prodromal motor signs of PD. Longitudinal diffusion tensor imaging before and after the development of prodromal motor PD showed higher fractional anisotropy in motor cortex and corticospinal tract compared to controls, indicating adaptive structural changes in motor networks in concert with nigrostriatal dopamine loss. Histological analyses of the white matter underlying the motor cortex showed progressive disorientation of axons with segmental replacement of neurofilaments with α-synuclein, enlargement of myelinating oligodendrocytes and increased density of their precursors. There was no loss of neurons in the motor cortex in early or late pathologically confirmed motor PD compared to controls, although there were early cortical increases in neuronal neurofilament light chain and myelin proteins in association with α-synuclein accumulation. Our results collectively provide evidence of a direct impact of PD on primary motor cortex and its output pathways that begins in the prodromal motor stage of PD with structural changes confirmed in early PD. These adaptive structural changes become considerable as the disease advances potentially contributing to motor PD.