Astrocyte dysfunction in Parkinson's Check for updates disease:from the perspectives of transmittedα-synuclein and genetic modulation

Parkinson's disease(PD)is a common neurodegenerative disorder that primarily affects the elderly.While the etiology of PD is likely multifactorial with the involvement of genetic,environmental,aging and other factors,α-synuclein(α-syn)pathology is a pivotal mechanism underlying the development of PD.In recent years,astrocytes have attracted considerable attention in the field.Although astrocytes perform a variety of physiological functions in the brain,they are pivotal mediators ofα-syn toxicity since they internalizeα-syn released from damaged neurons,and this triggers an inflammatory response,protein degradation dysfunction,mitochondrial dysfunction and endoplasmic reticulum stress.Astrocytes are indispensable coordinators in the background of several genetic mutations,including PARK7,GBA1,LRRK2,ATP13A2,PINK1,PRKN and PLA2G6.As the most abundant glial cells in the brain,functional astrocytes can be replenished and even converted to functional neurons.In this review,we discuss astrocyte dysfunction in PD with an emphasis onα-syn toxicity and genetic modulation and conclude that astrocyte replenishment is a valuable therapeutic approach in PD.

Expanding Views of Mitochondria in Parkinson's Disease: Focusing on PINK1 and GBA1 Mutations

A new conceptual model has been proposed for Parkinson's disease(PD)pathogenesis,which can be divided into triggering,facilitating,and aggravating processes[1].Mitochondria are believed to participate in all three phases:pesticides(one of the definite triggers in PD pathogenesis)inhibit mitochondrial complex I(MCI).

Iron, Dopamine, and α-Synuclein Interactions in at-Risk Dopaminergic Neurons in Parkinson's Disease

Parkinson’s disease(PD)is recognized as the second most common neurodegenerative disorder after Alzheimer disease.Although a fascinating 200-year journey of research has revealed the multifaceted nature of PD[1,2],its fundamental features are the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc)and depletion of dopamine(DA)in the striatum.Iron accumulates in normal brains with aging.Such

Breakthrough in Structural and Functional Dissection of the Hypothalamo-Neurohypophysial System

The projections from hypothalamic magnocellular neuroendocrine cells(MNCs)to the posterior pituitary(PPi)are traditionally defined as the hypothalamo-neurohy-pophysial system(HNS),which releases oxytocin(OXT)and arginine vasopressin(AVP)into the blood stream to regulate peripheral function[1].Recently,accumulating evidence has confirmed that OXT and AVP are not only involved in peripheral regulation[2],but also contribute to various central actions[3,4],such as memory and social and stress-related behaviors[5].However,peripherally released OXT and AVP rarely cross the blood-brain barrier and return to the central nervous system.So,whether and how they exert central effects remain to be elucidated.It is supposed that MNCs projecting to the PPi also have collaterals projecting centrally,and these might be responsible for the central actions of OXT and AVP.But there has been no cell-type-specific dissection of the hypothalamic MNC projections,due to the limited methods and techniques for imaging and manipulation.

Linking Genetic Risks to Pathologicalα-Synuclein Transmission in Parkinson's Disease

Misfoldedα-synuclein(α-syn)hallmarks the neuropathological characteristics of Parkinson's disease(PD)and acts as a"pathological seed"that promotes the progression of the disease[1].About 15%of PD patients have a family history,5%-10%have a monogenic disorder with a Mendelian pattern of inheritance[2],and>90 independent risk signals identified by genome-wide association studies(GWASs)can be used to explain the non-monogenic risk of PD[3].

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

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 involved in motor control, executive functions, motivation, arousal, reinforcement, and reward [1]. The ongoing tonic levels of dopamine release in the dorsal striatum are thought to be important for the regulation of movement. Because of the dopamine depletion in the striatum, movement is affected in PD. The typical motor symptoms consist of poverty of movement, tremor at rest, rigidity, and postural instability. Meanwhile, pre-motor symptoms, including hyposmia, constipation, depression, and REM sleep behavior disorder, have been suggested to precede these typical motor symptoms by years [2]. It is usually proposed to alleviate these symptoms via boosting the levels of dopamine in PD. However, this may not be the case.

Axonal Iron Transport might Contribute to Iron Deposition in Parkinson’s Disease

More and more evidence has suggested that iron deposition in the substantia nigra,which is correlated with motor and cognitive dysfunction,is an important trigger factor,potential biomarker,and therapeutic target for Parkinson's disease(PD)[1-3].Although the cellular mechanisms of nigral iron deposition have been well investigated,the exactly mechanisms,especially the origin of the increased nigral iron,have not been fully elucidated.

Alpha-Synuclein Handling by Microglia: Activating, Combating,and Worsening

Neuroinflammation and a-synuclein (a-syn) aggregation are both neuropathological hallmarks of Parkinson’s disease (PD). Microglia are crucial participants in eliciting neuroinflammatory responses themselves, as well as modulating neurotoxic activity in astrocytes, therefore forming a pathway to neurodegeneration induced by both central and peripheral insults [1, 2].

Dlg1 Knockout Inhibits Microglial Activation and Alleviates Lipopolysaccharide-Induced Depression-Like Behavior in Mice

Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polarization and the function of K?channels,which are reported to regulate the activation of microglia.However,little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis.In this study,we found that Dlg1 knockdown suppressed lipopolysaccharide(LPS)-induced inflammation by downregulating the activation of nuclear factor-jB signaling and the mitogen-activated protein kinase pathway in microglia.Moreover,using an inducible Dlg1 microglia-specific knockout(Dlg1flox/flox;CX3CR1CreER)mouse line,we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depressionlike behavior.In summary,our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.

Calcium Homeostasis in Parkinson’s Disease:From Pathology to Treatment

Disturbances of Ca^(2+)homeostasis have been reported to be associated with the development of Parkinson's disease(PD)(Fig.1),which is characterized by the selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta(SNpc).Different from the dopaminergic neurons in the ventral tegmental area(VTA),which mainly rely on hyperpolarization-activated cyclic nucleotide-gated/voltagegated channels for pacing and have a strong Ca^(2+)-buffering capacity.

A Novel Potassium Nanosensor Powers up the Detection of Extracellular K+ Dynamics in Neuroscience

Potassium ions(K+),the pivotal cations for membrane potential,are particularly important for maintaining the physiological function of neurons[1].When the concentration of extracellular K+([K+]o)is pathologically changed,the intrinsic neuronal excitability and synaptic transmission are also altered,which have profound implications for many neurological disorders such as epilepsy,Parkinson's disease,and emotional disorders[2-4].

Targeting the Cuneiform Nucleus in Parkinson’s Disease: Option to Improve Locomotor Activity

Parkinson's disease(PD)is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc),accompanied by severe locomotor deficits[1].Deep brain stimulation(DBS)mainly targeting the subthalamic nucleus and the internal segment of the globus pallidus has now been clinically used to improve the motor symptoms of PD patients.However,these targets do not relieve the serious postural instability and freezing of gait.The mesencephalic locomotor region(MLR)plays a key role in controlling locomotion[2,3].

Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing

Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection.As such,it is highly desired to design a nanocomposite hydrogel with excellent antibacterial activity to achieve high wound closure effectiveness.Here,based on ultrasound-triggered piezocatalytic therapy,a multifunctional hydrogel is designed to promote bacteria-infected wound healing.Under ultrasonic vibration,the surface of barium titanate(BaTiO_(3),BT)nanoparticles embedded in the hydrogel rapidly generate reactive oxygen species(ROS)owing to the established strong built-in electric field,endowing the hydrogel with superior antibacterial efficacy.This modality shows intriguing advantages over conventional photodynamic therapy,such as prominent soft tissue penetration ability and the avoidance of serious skin phototoxicity after systemic administration of photosensitizers.Moreover,the hydrogel based on N-[tris(hydroxymethyl)methyl]acrylamide(THM),N-(3-aminopropyl)methacrylamide hydrochloride(APMH)and oxidized hyaluronic acid(OHA)exhibits outstanding self-healing and bioadhesive properties able to accelerate full-thickness skin wound healing.Notably,compared with the widely reported mussel-inspired adhesive hydrogels,OHA/THM-APMH hydrogel due to the multiple hydrogen bonds from unique tri-hydroxyl structure overcomes the shortage that catechol groups are easily oxidized,giving it long-term and repeatable adhesion performance.Importantly,this hybrid hydrogel confines BT nanoparticles to wound area and locally induced piezoelectric catalysis under ultrasound to eradicate bacteria,markedly improving the therapeutic biosafety and exhibits great potential for harmless treatment of bacteria-infected tissues.

Ghrelin Reduces A-Type Potassium Currents in Dopaminergic Nigral Neurons via the PLC/PKCδPathway

Dear Editor,Ghrelin,an endogenous ligand of growth hormone secretagogue receptor 1a(GHS-R1a),is a 28-amino-acid peptide that regulates growth hormone secretion,metabolism,food intake,mood,cognition,memory,and neuroprotection[1-3].