Nigrostriatal Research Articles

Lead Phytomolecules for Treating Parkinson's Disease.

One percent of persons over 65 years of age suffer from Parkinson's disease, a neurological ailment marked by dopaminergic neurons in the nigrostriatal pathway gradually dying and being depleted in the striatum. Parkin and PINK1 gene mutations, which are essential for mitophagy and impair mitochondrial function, are the cause of it. Parkinson's disease is linked to a number of motor and impairment disorders, including bradykinesia, rigid muscles, tremor at rest, and imbalance. Numerous signaling pathways, including α-synuclein aggregation, lead to age-related decline in proteolytic defense systems. Parkinson's disease etiology involves oxidative stress, ferroptosis, mitochondrial failure, and neuroinflammation. Parkinson's disease is significantly influenced by neuroinflammation, which is a result of both innate and adaptive immune responses. The purpose of studying mechanisms and phytomolecules is to assist researchers in creating therapies for Parkinson's disease. Phytomolecules, like curcumin, β- amyrin, berberine, capsaicin, and gentisic acid, exert neuroprotective properties by reducing ROS levels, lessening α-synuclein-induced toxicity, and shielding the cells from apoptosis. In conclusion, the studies presented here provide valuable insights into the potential of various medications for Parkinson's disease treatment. By understanding the mechanisms behind these treatments, researchers can develop more effective treatments for PD.

The Potential Role of Dopamine Pathways in the Pathophysiology of Depression: Current Advances and Future Aspects.

Depression is a serious mental health disorder that impacts more than 350 million individuals globally. While the roles of serotonin and norepinephrine in depression have been extensively studied, the importance of dopaminergic pathways-essential for mood, cognition, motor control, and endocrine function-often gets overlooked. This review focuses on four major dopamine (DA) circuits: the mesolimbic (MLP), mesocortical (MCP), nigrostriatal (NSP), and thalamictuberoinfundibular pathways (TTFP), and their roles in depression. The MLP, which is key to reward processing, is linked to anhedonia, a primary depression symptom. The MCP, projecting to the prefrontal cortex, affects cognitive issues like impaired attention and decision-making. The NSP, mainly responsible for motor control, is related to psychomotor retardation in depression, while the TTFP manages neuroendocrine responses, which are often disrupted in stress-related depressive conditions. Current antidepressant treatments mainly target serotonin and norepinephrine systems but tend to be less effective for patients with DArgic dysfunction, leading to treatment resistance. This review underscores emerging evidence that suggests targeting DArgic pathways could improve treatment outcomes, especially for symptoms like anhedonia and cognitive deficits that conventional therapies often fail to address. Future research should aim to combine advancements in neuroimaging, optogenetics, and genetic studies to better map DArgic pathways and create personalized treatment plans. This review highlights the potential for new therapies that focus on DA systems, which could pave the way for more effective and tailored approaches to treating depression.

Dopamine D4 receptors in the lateral habenula regulate anxiety-related behaviors in a rat model of Parkinson's disease

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopamine (DA) and 5-hydroxytryptamine (5-HT) containing systems, which are implicated in the pathophysiology of anxiety, it is not clear how activation and blockade of LHb D4 receptors affects anxiety-like behaviors, particularly in Parkinson’s disease related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, which attribute to hyperactivity of LHb neurons and decrease in the level of DA in the medial prefrontal cortex (mPFC), amygdala and ventral hippocampus (vHip) compared to sham-operated rats. Intra-LHb injection of D4 receptor agonist A412997 induced or increased the expression of anxiety-like behaviors, while injection of D4 receptor antagonist L741742 showed anxiolytic effects in sham-operated and the SNc-lesioned rats. However, the doses producing behavioral effects in the lesioned rats were higher than those of sham-operated rats. Intra-LHb injection of A412997 increased firing rate of LHb neurons, and decreased levels of DA and 5-HT in the mPFC, amygdala and vHip; conversely, L741742 decreased firing rate of LHb neurons, and increased levels of DA and 5-HT in two groups of rats. Compared to sham-operated rats, the duration of A412997 and L741742 action on the firing rate of neurons was markedly shortened in the lesioned rats. Collectively, these findings suggest that D4 receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway down-regulates function and/or expression of these receptors.

Characterizing Secondary and Atypical Parkinsonisms: Defining Features and Clinical Variability

Parkinsonism is a clinical syndrome characterized by akinesia/bradykinesia, muscle rigidity, resting tremor, and postural instability. Within the group of parkinsonisms is Parkinson’s disease, also known as neurodegenerative parkinsonian syndrome. The group of atypical parkinsonisms was established due to the existence of sporadic parkinsonisms that do not share the exact etiology of Parkinson’s disease. Additionally, parkinsonisms that arise from causes other than neurodegeneration have been classified as secondary parkinsonisms. With this in mind, given the diversity of etiologies that can trigger parkinsonism, it is crucial to understand the symptomatology and its relationship with the basal ganglia (including damage to the nigrostriatal pathway, neuroinflammation, and neuronal damage). Only then will it be possible to propose appropriate treatments for each variant of parkinsonism.

Modeling early phenotypes of Parkinson’s disease by age-induced midbrain-striatum assembloids

Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.

Substantia nigra alterations in mice modeling Parkinson’s disease

Substantia nigra alterations in mice modeling Parkinson’s disease

Modulating the cholinergic system—Novel targets for deep brain stimulation in Parkinson's disease

AbstractParkinson's disease (PD) is the second‐fastest growing neurodegenerative disease in the world. The major clinical symptoms rigor, tremor, and bradykinesia derive from the degeneration of the nigrostriatal pathway. However, PD is a multi‐system disease, and neurodegeneration extends beyond the degradation of the dopaminergic pathway. Symptoms such as postural instability, freezing of gait, falls, and cognitive decline are predominantly caused by alterations of transmitter systems outside the classical dopaminergic axis. While levodopa and deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus effectively address PD primary motor symptoms, they often fall short in mitigating axial symptoms and cognitive impairment. Along these lines, the cholinergic system is increasingly recognized to play a crucial role in governing locomotion, postural stability, and cognitive function. Thus, there is a growing interest in bolstering the cholinergic tone by DBS of cholinergic targets such as the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (NBM), aiming to alleviate these debilitating symptoms resistant to traditional treatment strategies targeting the dopaminergic network. This review offers a comprehensive overview of the role of cholinergic dysfunction in PD. We discuss the impact of PPN and NBM DBS on the management of symptoms not readily accessible to established DBS targets and pharmacotherapy in PD and seek to provide guidance on patient selection, surgical approach, and stimulation paradigms.image

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

AimsThe standard Parkinson's disease (PD) treatment is L-3,4-dihydroxyphenylalanine (L-DOPA); however, its long-term use may cause L-DOPA-induced dyskinesia (LID). Aberrant activation of medium spiny neurons (MSNs) contributes to LID, and MSN excitability is regulated by dopamine D3 receptor (D3R) and ATP-sensitive potassium (KATP) channel activity. Nevertheless, it remains unclear if D3R and KATP channels may be linked in the context of LID. MethodsWild-type and tyrosine hydroxylase (TH)-specific Kir6.2 knockout mice were injected with 6-hydroxydopamine (6-OHDA) to generate a PD mouse model, then chronically treated with L-DOPA to induce LID. Analyses included immunohistochemical staining, biochemical endpoints, and behavior tests. The mechanisms by which D3R/KATP channels regulate LID in the PD/LID mouse model were probed by treatment with a D3R antagonist, KATP channel opener and glycogen synthase kinase 3β (GSK3β) inhibitor, followed by evaluation of abnormal involuntary movements (AIMs). Key findingsThe D3R antagonist FAUC365 alleviated LID, reducing AIMs and protecting against degeneration of the nigrostriatal pathway, which occurred through a direct interaction between D3Rs and KATP channels. In line with this mechanism, activation of D3R/GSK3β signaling increased KATP channel expression in the striatum of PD/LID mice. Additionally, the KATP channel opener Diz slowed LID progression and preserved nigrostriatal projections. Consistently, mice with TH-specific knockout of Kir6.2 exhibited reduced PD-like symptoms and less severe LID. SignificanceD3Rs act through GSK3β signaling to regulate expression of KATP channels, which may subsequently modulate LID. Inhibition of KATP channels in TH-positive cells is sufficient to reduce AIMs in a mouse model of PD/LID.

Effects of Acute Haloperidol Treatment on Dopaminergic Markers, GAD67, and A2A Receptors in Rats with High and Low VCMs.

Vacuous chewing movements (VCM) have been utilized as an experimental model of orofacial dyskinesia (OD) in rodents to study the underlying molecular mechanisms related to tardive dyskinesia (TD). This study aimed to investigate if the acute treatment with haloperidol can alter components of the dopaminergic synapse or its modulators such as glutamic acid decarboxylase (GAD67) and adenosine 2A (A2A) receptor. Furthermore, to evaluate if changes in molecular markers are associated with the number of VCMs induced by haloperidol in rats it is proposing a method to classify the animals into High and Low VCM groups. Here, we treated rats with haloperidol decanoate (single injection, intramuscularly, 28mg/Kg of unconjugated haloperidol) and evaluated the number of VCMs after 4 weeks. Haloperidol-treated rats were divided into three groups (Low, High, and Spontaneous VCM) according to the evaluation of the VCM profile proposed here. After, dopamine (DA) levels, monoamine oxidase (MAO) activity, and the immunoreactivity of tyrosine hydroxylase (TH), dopamine transporter (DAT), D2 receptor, GAD67, and A2A were determined in brain structures. No significant differences were found in DA levels, MAO activity, and immunoreactivity of the TH, DAT, D2 receptor, GAD67, and A2A receptor in brain structures. VCM intensity was correlated with TH immunoreactivity in Sn in the High VCM group while it was inversely correlated with the immunoreactivity of the A2A receptor in the striatum of the Spontaneous VCM group. Other significant correlations were found considering the VCM profile suggesting that High VCM after acute haloperidol treatment seems to be associated with the lack of ability to reorganize the neurotransmission in the nigrostriatal pathway. Further studies could clarify the main targets involved in the motor side effects of antipsychotics. The present study demonstrated an easy way to separate the animals into High and Low VCMs.

Possible Potentiating Effects of Combined Administration of Alcohol, Caffeine, and Nicotine on In Vivo Dopamine Release in Addiction-Related Circuits Within the CNS of Rats.

Studies that assess the effects of the interaction of psychoactive substances on dopamine release, the key neurotransmitter in the neurochemical and behavioral effects related to drug consumption, are crucial to understand both their roles and the dysfunctions they produce in the central nervous system. We evaluated the effects of individual and combined administration of the three most widely consumed psychoactive substances in the world, ethanol, caffeine, and nicotine, on dopaminergic neurotransmission in three brain regions of rats related to addiction: the prefrontal cortex (PFC), the nucleus accumbens (NAcc), and the dorsal striatum. The dopamine levels were measured in vivo by cerebral microdialysis associated with HPLC-ED. We observed that local administration of a single concentration of caffeine (5 mM) or nicotine (5 mM) significantly increased the dopamine levels in all three areas studied, while ethanol (300 mM) increased them in the NAcc and striatum. Perfusion of nicotine + caffeine produced a synergistic effect in both the NAcc and striatum, with increases in the in vivo dopamine release greater than the sum of the effects of both substances. When administering the combination of nicotine + caffeine + ethanol, we observed an additive effect in the NAcc, while in the PFC we observed a synergistic effect. Our results support the stimulating effects of caffeine, nicotine, and ethanol on the brain reward system. In addition, we also observed that the administration of different mixtures of these substances produces synergistic and additive effects on the release of dopamine in the mesocortical and nigrostriatal systems.

The Role of Dopamine in Impulsivity and Substance Abuse: A Narrative Review

Substance use disorder (SUD), based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), is defined by symptoms caused by utilizing a substance that a person continues taking despite its negative effects. Impulsive decision making is commonly defined as a reduced ability to choose a delayed large reward instead of a small immediate reward. Dopamine has been implicated as a prominent neurotransmitter implicated in the development and pattern of addiction and impulsivity, especially in regard to substance use disorder. Discovery as a key player in the development of addiction dates to the 1950s, with a study performed by Olds and Milner on rats placed in a Skinner box. Their original discovery is part of the beginning of what would become the search into the main mechanistic source of addiction, and how exactly it works at a cellular, physiological, and psychological level. The dopaminergic pathways of our brains are well-studied. It is well established that most of the dopaminergic neurons of the brain are located in the ventral mid-brain and consists of four main pathways: mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways. Dopamine acts various receptors, with dopamine (D) receptors 1, 2, and 3 playing a major role in motor function and receptors D1 and D2 playing a major role in reward. There are additional studies warranted, especially finding ways to manipulate the dopaminergic system to treat addiction disorders of all varieties. The focus of the present investigation is to delve into the current literature regarding dopamine and its clinical implications in substance use disorder and impulsive behavior.

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

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

Functional PET/MRI reveals active inhibition of neuronal activity during optogenetic activation of the nigrostriatal pathway.

The dopaminergic system is a central component of the brain's neurobiological framework, governing motor control and reward responses and playing an essential role in various brain disorders. Within this complex network, the nigrostriatal pathway represents a critical circuit for dopamine neurotransmission from the substantia nigra to the striatum. However, stand-alone functional magnetic resonance imaging is unable to study the intricate interplay between brain activation and its molecular underpinnings. In our study, the use of a functional [fluorine-18]2-fluor-2-deoxy-d-glucose positron emission tomography approach, simultaneously with blood oxygen level-dependent functional magnetic resonance imaging, provided an important insight that demonstrates an active suppression of the nigrostriatal activity during optogenetic stimulation. This result increases our understanding of the molecular mechanisms of brain function and provides an important perspective on how dopamine influences hemodynamic responses in the brain.

Phosphodiesterase inhibition and Gucy2C activation enhance tyrosine hydroxylase Ser40 phosphorylation and improve 6-hydroxydopamine-induced motor deficits

BackgroundParkinson’s disease is characterized by a progressive loss of dopaminergic neurons in the nigrostriatal pathway, leading to dopamine deficiency and motor impairments. Current treatments, such as L-DOPA, provide symptomatic relief but result in off-target effects and diminished efficacy over time. This study explores an alternative approach by investigating the activation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Specifically, we explore the effects of phosphodiesterase (PDE) inhibition and guanylate cyclase-C (GUCY2C) activation on tyrosine hydroxylase Ser40 phosphorylation and their impact on motor behavior in a 6-hydroxydopamine (6-OHDA) Parkinson's disease model.ResultsOur findings demonstrate that increasing cyclic nucleotide levels through PDE inhibition and GUCY2C activation significantly enhances tyrosine hydroxylase Ser40 phosphorylation. In a Pitx3-deficient mouse model, which mimics the loss of dopaminergic neurons seen in Parkinson’s disease, Ser40 phosphorylation remained manipulable despite reduced tyrosine hydroxylase protein levels. Moreover, we observed no evidence of tyrosine hydroxylase degradation due to Ser40 phosphorylation, challenging previous reports. Furthermore, both PDE inhibition and GUCY2C activation resulted in improved motor behavior in the 6-OHDA Parkinson’s disease mouse model, highlighting the potential therapeutic benefits of these approaches.ConclusionsThis study underscores the therapeutic potential of enhancing tyrosine hydroxylase Ser40 phosphorylation to improve motor function in Parkinson’s disease. Both PDE inhibition and GUCY2C activation represent promising non-invasive strategies to modulate endogenous dopamine biosynthesis and address motor deficits. These findings suggest that targeting cyclic nucleotide pathways could lead to novel therapeutic approaches, either as standalone treatments or in combination with existing therapies like L-DOPA, aiming to provide more durable symptom relief and potentially mitigate neurodegeneration in Parkinson's disease.

Nigrostriatal tract defects in mice with aromatic l-amino acid decarboxylase deficiency

The development of the nigrostriatal dopaminergic (DA) pathway in the brain involves many transcriptional and chemotactic molecules, and a deficiency of these molecules can cause nigrostriatal tract defects. However, the role of the end product, dopamine, in nigrostriatal pathway development has not been described. In the present study, we analyzed a mouse model of congenital dopamine and serotonin deficiency, namely, the aromatic l-amino acid decarboxylase (AADC) deficiency (DdcKI) mouse model. We found via tyrosine hydroxylase (TH) immunofluorescence staining that the number of DA fibers in the stratum of 14-day-old DdcKI mice decreased. In TH-stained cleared whole brains of DdcKI mice, the numbers of DA neurons in the substantia nigra (SN) and the number of DA nerve bundles leaving the SN were both normal. However, we found that the nigrostriatal bundles in DdcKI mice were dispersed, taking aberrant routes to the striatum and spreading over a wide area. The total volume occupied by the nigrostriatal tract was increased, and the fraction of TH staining in the tract was decreased in DdcKI mice. Single-nucleus RNA sequencing analysis for mice 0, 7, and 14 days of age, revealed delayed axonogenesis and synapse formation in the striatum of DdcKI mice. The CellChat program inferred less cell–cell communication between striatal D1/D2 neurons but increased cell–cell communication involving neural precursors in DdcKI mice. Therefore, a congenital deficiency in dopamine affects nigrostriatal axon extension and striatal innervation. These nigrostriatal tract defects may limit the treatment efficacy for patients with TH or AADC deficiency.

Small Molecules, α-Synuclein Pathology, and the Search for Effective Treatments in Parkinson's Disease.

Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders.

Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein

Loss-of-function mutations in the ATP13A2 (PARK9) gene are implicated in early-onset autosomal recessive Parkinson's disease (PD) and other neurodegenerative disorders. ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase that is highly expressed in brain and specifically within the substantia nigra pars compacta (SNc). Recent studies have revealed its normal role as a lysosomal polyamine transporter, although its contribution to PD-related pathology remains unclear. Cellular studies report that ATP13A2 can regulate α-synuclein (α-syn) secretion via exosomes. However, the relationship between ATP13A2 and α-syn in animal models remains inconclusive. ATP13A2 knockout (KO) mice exhibit lysosomal abnormalities and reactive astrogliosis but do not develop PD-related neuropathology. Studies manipulating α-syn levels in mice lacking ATP13A2 indicate minimal effects on pathology. The delivery of α-syn preformed fibrils (PFFs) into the mouse striatum is a well-defined model to study the development and spread of α-syn pathology. In this study we unilaterally injected wild-type (WT) and homozygous ATP13A2 KO mice with mouse α-syn PFFs in the striatum and evaluated mice for neuropathology after 6 months. The distribution, spread and extent of α-syn aggregation in multiple regions of the mouse brain was largely independent of ATP13A2 expression. The loss of nigrostriatal pathway dopaminergic neurons and their nerve terminals induced by PFFs were equivalent in WT and ATP13A2 KO mice. Reactive astrogliosis was induced equivalently by α-syn PFFs in WT and KO mice but was already significantly higher in ATP13A2 KO mice due to pre-existing reactive gliosis. We did not identify asymmetric motor disturbances, microglial activation, or axonal damage induced by α-syn PFFs in WT or KO mice. Although α-syn PFFs induce an increase in lysosomal number in the SNc in general, TH-positive dopaminergic neurons did not exhibit either increased lysosomal area or intensity, regardless of genotype. Our study evaluating the spread of α-syn pathology reveals no exacerbation of α-syn pathology, neuronal loss, astrogliosis or motor deficits in ATP13A2 KO mice, suggesting that selective lysosomal abnormalities resulting from ATP13A2 loss do not play a major role in α-syn clearance or propagation in vivo.

The therapeutic use of clonal neural stem cells in experimental Parkinson´s disease

BackgroundParkinson´s disease (PD), the second most common neurodegenerative disease in the world, is characterized by the death or impairment of dopaminergic neurons (DAn) in the substantia nigra pars compacta and dopamine depletion in the striatum. Currently, there is no cure for PD, and treatments only help to reduce the symptoms of the disease, and do not repair or replace the DAn damaged or lost in PD. Cell replacement therapy (CRT) seeks to relieve both pathological and symptomatic PD manifestations and has been shown to have beneficial effects in experimental PD models as well as in PD patients, but an apt cell line to be used in the treatment of PD has yet to be established. The purpose of this study was to examine the effects of the transplantation of hVM1 clone 32 cells, a bankable line of human neural stem cells (hNSCs), in a PD mouse model at four months post-transplant.MethodsAdult (five month-old) C57BL/6JRccHsd male mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and subsequently transplanted with hVM1 clone 32 cells, or buffer, in the left striatum. Four months post-transplant, behavioral effects were explored using the open field and paw print tests, and histological analyses were performed.ResultsTransplantation of hVM1 clone 32 cells rescued dopaminergic nigrostriatal populations in adult Parkinsonian mice. Motor and neurological deterioration were observed in buffer-treated mice, the latter of which had a tendency to improve in hNSC-transplanted mice. Detection of mast cell migration to the superficial cervical lymph nodes in cell-transplanted mice denoted a peripheral effect. Transplantation of hNSCs also rescued neuroblast neurogenesis in the subgranular zone, which was correlated with dopaminergic recovery and is indicative of local recovery mechanisms.ConclusionsIn this proof-of-concept study, the transplantation of hVM1 clone 32 cells provided neuroprotection in adult Parkinsonian mice by restoring the dopaminergic nigrostriatal pathway and hippocampal neurogenesis, demonstrating the efficacy of cell replacement therapy as a treatment for PD.

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

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

Oral Trehalose Intake Modulates the Microbiota–Gut–Brain Axis and Is Neuroprotective in a Synucleinopathy Mouse Model

Parkinson’s disease (PD) is a neurodegenerative disease affecting dopaminergic neurons in the nigrostriatal and gastrointestinal tracts, causing both motor and non-motor symptoms. This study examined the neuroprotective effects of trehalose. This sugar is confined in the gut due to the absence of transporters, so we hypothesized that trehalose might exert neuroprotective effects on PD through its action on the gut microbiota. We used a transgenic mouse model of PD (PrP-A53T G2-3) overexpressing human α-synuclein and developing GI dysfunctions. Mice were given water with trehalose, maltose, or sucrose (2% w/v) for 6.5 m. Trehalose administration prevented a reduction in tyrosine hydroxylase immunoreactivity in the substantia nigra (−25%), striatum (−38%), and gut (−18%) in PrP-A53T mice. It also modulated the gut microbiota, reducing the loss of diversity seen in PrP-A53T mice and promoting bacteria negatively correlated with PD in patients. Additionally, trehalose treatment increased the intestinal secretion of glucagon-like peptide 1 (GLP-1) by 29%. Maltose and sucrose, which break down into glucose, did not show neuroprotective effects, suggesting glucose is not involved in trehalose-mediated neuroprotection. Since trehalose is unlikely to cross the intestinal barrier at the given dose, the results suggest its effects are mediated indirectly through the gut microbiota and GLP-1.