Non-coding RNAs and stem cells:the dream team for neural regeneration in Parkinson’s disease?

Parkinson’s disease(PD)is a widely spread neurodegenerative movement disorder,affecting approximately 10 million people worldwide.It is primarily caused by the loss of dopaminergic neurons in the substantia nigra,which causes decreased secretion of dopamine leading to tremors,bradykinesia and rigid muscle movement.The development of PD is complex and needs to be better understood.Current treatment strategies primarily involve targeting disease symptoms,however,since there is a continuous loss of dopaminergic neurons in the brain,PD appears to be incurable.Moreover,treatment strategies often carry severe side effects related to dopamine production,where too little or too much can cause debilitating issues such as dyskinesia.The pool of neural stem/progenitor cells(NSCs)located in sub-ventricular zone and hippocampal dentate gyrus,proliferate and are responsible to give rise to neurons and glia in response to any cellular damage.Though this activation of NSCs is highly regulated,it is insufficient to overcome the loss of dopaminergic neurons in PD.In this line,non-coding RNAs(ncRNAs)are involved in the underlying mechanisms of PD and are known to have important functional roles in neural regeneration(Acharya et al.,2020).Thus,the study of ncRNAs in NSC activation and adult neurogenesis post PD development is an extremely attractive area of research with significant clinical application potential.     

Neural grafting for Parkinson's disease: challenges and prospects

Parkinson's disease (PD) is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia nigra. The motor disorder responds well to dopamine-replacement therapies, though these result in significant adverse effects due to non-physiolog-ical release of dopamine in the striatum, and off-target effects. Cell-based regenerative treatments offer a potential means for targeted replacement of dopamine, in a physiological manner. Dopaminergic neurons for cell-based therapies can be obtained from several sources. Fetal ventral mesencephalon tissue contains dopaminergic neuron progenitors, and has been transplanted into the striatum of PD patients with good results in a number of cases. However, the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical setting. Induced plu-ripotent stem cells can be used to generate dopaminergic neurons for transplantation, providing a source of autologous tissue for grafting. This approach means that challenges associated with allografts, such as the potential for immune rejection, can be circumvented. However, the associated cost and difficulty in producing a standardized product from different cell lines means that, at present, this approach is not com-mercially viable as a cell-based therapy. Dopaminergic neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson's disease, with trials due to commence in the next few years. Though there are ethical considerations to take into account when using embryonic tissue, the possibility of producing a standardized, optimized cell product means that this approach can be both effective, and commercially viable.     

Gene therapy in Parkinson’s disease:targeting the endplasmic reticulum proteostasis network

<正>Parkinson’s disease(PD)is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta(SNpc)results in a severe and gradual depletion of dopamine content in the striatum,a phenomena that is responsible for the characteristic motor symptoms of this disease.There is no cure for PD and available treatments only aim to restore dopamine deficits.Administration of the dopamine precursor Levodopa(L-DOPA)is the main temporal palliative treatment that increases overall dopamine levels.However,its chronic use limits its effectiveness and generates a number of adverse effects such as debilitating dyskinesia.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson’s disease☆

Parkinson＇s disease （PD） is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor （BDNF） mRNA （20%） than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

Progression of motor symptoms in Parkinson’s disease

Parkinson’s disease(PD)is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms-rigidity,bradykinesia and tremor-due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms.However,the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.     

Magnetic resonance imaging markers for early diagnosis of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by selective and progressive degeneration, as well as loss of dopaminergic neurons in the substantia nigra. In PD, approximately 60-70% of nigrostriatal neurons are degenerated and 80% of content of the striatal dopamine is reduced before the diagnosis can be established according to widely accepted clinical diagnostic criteria. This condition describes a stage of disease called "prodromal", where non-motor symptoms, such as olfactory dysfunction, constipation, rapid eye movement behaviour disorder, depression, precede motor sign of PD. Detection of prodromal phase of PD is becoming an important goal for determining the prognosis and choosing a suitable treatment strategy. In this review, we present some non-invasive instrumental approaches that could be useful to identify patients in the prodromal phase of PD or in an early clinical phase, when the first motor symptoms begin to be apparent. Conventional magnetic resonance imaging (MRI) and advanced MRI techniques, such as magnetic resonance spectroscopy imaging, diffusion-weighted and diffusion tensor imaging and functional MRI, are useful to differentiate early PD with initial motor symptoms from atypical parkinsonian disorders, thus, making easier early diagnosis. Functional MRI and diffusion tensor imaging techniques can show abnormalities in the olfactory system in prodromal PD.     

Cortical regulation of striatal projection neurons and interneurons in a Parkinson's disease rat model

Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 k Da, calbindin, and μ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson's disease.     

Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration： implications for the pathogenesis of Parkinson＇s disease

While the cause of dopaminergic neuronal cell death in Parkinson＇s disease（PD）is not yet understood,many endogenous molecules have been implicated in its pathogenesis.β-phenethylamine（β-PEA）,a component of various food items including chocolate and wine,is an endogenous molecule produced from phenylalanine in the brain.It has been reported recently that long-term administration ofβ-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins.The toxicity ofβ-PEA has been linked to the production of hydroxyl radical（.OH）and the generation of oxidative stress in dopaminergic areas of the brain,and this may be mediated by inhibition of mitochondrial complex-I.Another significant observation is that administration ofβ-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents.However,no reports are available on the extent of dopaminergic neuronal cell death after administration ofβ-PEA.Based on the literature,we set out to establishβ-PEA as an endogenous molecule that potentially contributes to the progressive development of PD.The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption ofβ-PEA-containing foods is proposed here.Thus,long-term over-consumption of food items containingβ-PEA could be a neurological risk factor having significant pathological consequences.     

Designing nanocarriers to overcome the limitations in conventional drug administration for Parkinson’s disease

Neurodegenerative diseases(NDs)have become one of the leading causes of death and disability worldwide,and cause enormous pain and suffering for both patients and their families.Some of the most common NDs include Alzheimer’s disease,Parkinson’s disease(PD)and Huntington’s disease,among others(Feng,2020).PD is a widespread neurodegenerative disease that affects more than 10 million people worldwide(No author listed,2021).The direct cause of the disease is unknown,but it is characterized by the selective degeneration of dopaminergic neurons in the midbrain in the substantia nigra.This leads to the depletion of dopamine(3,4-dihydroxyphenethylamine,DA)in the striatum of patients,in addition to the existence of abnormalα-synuclein in nerve cells and the development of toxic protein aggregates in neurons called Lewy bodies,which causes muscle stiffness,slowness of movements and tremors.It is believed that a combination of genetic and environmental factors may be the cause of PD,but the exact reason for the disease is not yet fully understood.     

Interleukin 4-induced neuroprotection and regulation of microglia activation as a therapeutic approach in the MPTP model of Parkinson's disease

<正>Parkinson’s disease(PD)has been described as one of the most common neurodegenerative diseases affecting up to 2%of the worldwide population over 60 years of age.The hallmarks of PD are progressive loss of midbrain dopaminergic(m DA)neurons and a decrease in striatal dopamine levels,which result in typical clinical motor symptoms such as akinesia,resting tremor,rigidity,and gait impairments.Although the causes for PD are only partially understood and seem to be very heterogeneous,one of the common phenomenons observed in toxin-based animal models of PD as well as PD patients is a microglia-driven neuroinflammatory response,which is at least in part responsible for exacerbation of neuronal loss and worsening of clinical     

Cell replacement for Parkinson's disease:advances and challenges

<正>Parkinson’s disease(PD), characterized by the loss of dopaminergic(DA) neurons in the substantia nigra pars compacta(SNpc) of the midbrain, is a prototype neurological disease that is suitable for cellular replacement therapy. Levodopa has been utilized to replace the insufficient dopamine released by degenerating DA neurons since the 1960s and it remains the cornerstone of PD treatment. However, as the disease progresses,     

The Epigenome as a therapeutic target for Parkinson’s disease

Parkinsons disease(PD) is a common,progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons,aggregation of α-synuclein and motor symptoms.Current dopamine-replacement strategies provide symptomatic relief,however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients.There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD.Over recent years,there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients,and that epigenetic modulation is a promising therapeutic approach for PD.This article first discusses the present evidence implicating global,and dopaminergic neuron-specific,alterations in the methylome in PD,and the therapeutic potential of pharmacologically targeting the methylome.It then focuses on another mechanism of epigenetic regulation,histone acetylation,and describes how the histone acetyltransferase(HAT) and histone deacetylase(HDAC) enzymes that mediate this process are attractive therapeutic targets for PD.It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD,and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects.Finally,it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD,and the future research that will be required to determine and realise this therapeutic potential.     

Inhibition of microglial activation and induction of neurotrophic factors by flavonoids:a potential therapeutic strategy against Parkinson’s disease

<正>Parkinson’s disease(PD)is characterized by the progressive degeneration of dopaminergic(DA)neurons and a decrease in striatal dopamine,which is associated with clinical movement disorders including a tremor at rest,rigidity of the limbs,bradykinesia(slowness and paucity of voluntary movement)and postural instability(a tendency to fall even in the absence of     

A biophysical perspective on the unexplored mechanisms driving Parkinson’s disease by amphetamine-like stimulants

Epidemiological studies have reported an increased risk of Parkinson’s disease(PD)development in amphetamine-type stimulant users during their lifetime(Garwood et al.,2006;Rumpf et al.,2017).Protein inclusions mainly composed of misfolded and aggregatedα-synuclein are the pathological hallmark of PD and other disorders known as synucleinopathies.Molecular studies present evidence that amphetamine upregulatesα-synuclein synthesis in substantia nigra.The increment ofα-synuclein levels promotes its aggregation and amyloid fibril formation,increasing reactive oxygen species(ROS),and consequently dopamine oxidation(Wang and Witt,2014),known to be toxic for dopaminergic neurons involved in motor function and limbicmotor integration.Over the years,these damaged cells lose their functionality and may die precociously,depleting the reserve of neural cells necessary for the normal neurological function which contributes to the onset of PD,when a critical number of cells are lost(Garwood et al.,2006).Therefore,the use of amphetamine-type stimulants may be a trigger event in the development of PD and parkinsonism,in conjugation to other risk factors that a given individual may hold.Despite the evidence,a previous study suggests that there is not enough data to corroborate the loss of dopamine neurons due to human amphetamine-type stimulant exposure,and consequently its implication in the PD development(Kish et al.,2017).     

Calcium handling:a strategy to fight neurodegeneration in Alzheimer's disease

<正>In the last few years,preclinical and clinical studies identified the ventral tegmental area(VTA) as one of the first brain regions to be affected in the prodromal phase of Alzheimer’s disease(AD).The VTA is a deep midbrain nucleus rich in dopaminergic neurons that innervates and releases dopamine(DA) in several cortical and subcortical brain regions.DA plays a crucial role in the modulation of both cognitive and noncognitive functions and failure of its release underlies both cognitive...     

Pharmacogenetic activation of midbrain dopaminergic neurons induces hyperactivity

Dopaminergic neurons regulate and organize numerous important behavioral processes including motor activity.Consistently,manipulation of brain dopamine concentrations changes animal activity levels.Dopamine is synthesized by several neuronal populations in the brain.This study was carried out to directly test whether selective activation of dopamine neurons in the midbrain induces hyperactivity.A pharmacogenetic approach was used to activate midbrain dopamine neurons,and behavioral assays were conducted to determine the effects on mouse activity levels.Transgenic expression of the evolved hM3Dq receptor was achieved by infusing Creinducible AAV viral vectors into the midbrain of DATCre mice.Neurons were excited by injecting the hM3Dq ligand clozapine-N-oxide（CNO）.Mouse locomotor activity was measured in an open field.The results showed that CNO selectively activated midbrain dopaminergic neurons and induced hyperactivity in a dose-dependent manner,supporting the idea that these neurons play an important role in regulating motor activity.     

Transforming growth factor β1-mediated anti-inflammation slows progression of midbrain dopaminergic neurodegeneration in Parkinson's disease?

<正>Parkinson’s disease(PD)is characterized by the progressive loss of midbrain dopaminergic(m DA)neurons and a subsequent decrease in striatal dopamine levels,which cause the typical clinical motor symptoms such as muscle rigidity,bradykinesia and tremor.Although a subset of     

Dopamine in Parkinson’s Disease: Precise Supplementation with Motor Planning

正Parkinson’s disease (PD) is the second most common neurodegenerative disorder which mainly affects the motor system. The pathological characteristics of PD include the loss of dopaminergic neurons in the substantia nigra region and dopamine depletion in the striatum.Dopamine functions as a neurotransmitter that is