Kdm6a-CNN1 axis orchestrates epigenetic control of traumainduced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors.Despite extensive investigations into vascular senescence associated with aging and degenerative diseases,the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress,particularly its involvement in senescence-induced inflammation,remain insufficiently elucidated.In this study,we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury(SCI).Lysine demethylase 6A(Kdm6a),commonly known as UTX,emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells(SCMECs).Upregulation of UTX induces senescence in SCMECs,leading to an amplified release of proinflammatory factors,specifically the senescenceassociated secretory phenotype(SASP)components,thereby modulating the inflammatory microenvironment.Conversely,the deletion of UTX in endothelial cells shields SCMECs against senescence,mitigates the release of proinflammatory SASP factors,and promotes neurological functional recovery after SCI.UTX forms an epigenetic regulatory axis by binding to calponin 1(CNN1),orchestrating trauma-induced SCMECs senescence and SASP secretion,thereby influencing neuroinflammation and neurological functional repair.Furthermore,local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion,reinstating a local regenerative microenvironment and enhancing functional repair after SCI.In conclusion,targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion,alleviate neuroinflammation,and provide a novel treatment strategy for SCI repair.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Using microglia-derived extracellular vesicles to capture diversity of microglial activation phenotypes following neurological injury

Microglia are one of the three glial cell populations in the central nervous system(CNS),along with astrocytes and oligodendrocytes.While microglia are unique among brain cells due to their hematologic origin and perform immune functions similar to peripheral macrophages,they are not simply macrophages of the CNS.

Could mammalian inorganic polyphosphate be a crucial signaling molecule in neurological disorders?

Since the early stages of life on earth,cellular metabolism has evolved to adapt to fluctuations in nutrient and oxygen availability.In this context,mammals,which are probably the organisms that show one of the highest levels of metabolic complexity,have developed an elegant system that uses constant and rechargeable energy sources of modulate their metabolism.This homeostasis is especially important in the central nervous system,as neurons and other cells in the brain are highly susceptible to fluctuations in nutrients and oxygen availability.

Neuroprotective potential of traditional Ayurvedic Kadha:age-related neurological disorders:a comprehensive literature review

Despite modern medicine’s advancements,age-related neurological diseases like Alzheimer’s disease and Parkinson’s disease remain challenging due to high costs,side effects,and limited accessibility.Ayurveda,a traditional Indian medicine system,offers Kadha tea as a potential herbal option.This review explores Kadha’s components(basil(Ocimum basilicum L.),black pepper(Piper nigrum L.),Cinnamon(Cinnamomum verum J.Presl),ginger(Zingiber officinale Roscoe),and raisin(Vitis vinifera L.))and their interaction with various neurological disorders.Studies suggest Kadha exhibits anti-inflammatory,antioxidant,and antiviral properties,potentially impacting Alzheimer’s disease,Parkinson’s disease,neurotoxicity,neuroinflammation,and brain trauma.By focusing on specific disease mechanisms and Kadha’s intergrade effects,this review aims to elucidate its potential role in managing age-related neurological disorders.

Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be used to treat these disorders. We concluded that there are few clinical drugs that can improve the pathology these diseases by acting on potassium or calcium ions. Although a few novel ion-channelspecific modulators have been discovered, meaningful therapies have largely not yet been realized. The lack of target-specific drugs, their requirement to cross the blood–brain barrier, and their exact underlying mechanisms all need further attention. This review aims to explain the urgent problems that need research progress and provide comprehensive information aiming to arouse the research community's interest in the development of ion channel-targeting drugs and the identification of new therapeutic targets for that can increase the cure rate of nervous system diseases and reduce the occurrence of adverse reactions in other systems.

Neurological Manifestations of Vitamin B12 Deficiency: About a Case

The authors report a case of deficient sensory neuropathy secondary to vitamin B12 deficiency, diagnosed in the neurology department of the Sino-Central African Friendship University Hospital in Bangui. The diagnosis was made possible by electroneuromyography which showed subclinical neurological damage associated with hematological damage (anemia). Through this observation, we recall the diagnostic criteria of the disease in a context of difficult medical practice. .

Steel bar penetrating cervical spinal canal without neurological injury:A case report

BACKGROUND We report a rare case of cervical spinal canal penetrating trauma and review the relevant literatures.CASE SUMMARY A 58-year-old male patient was admitted to the emergency department with a steel bar penetrating the neck,without signs of neurological deficit.Computed tomography(CT)demonstrated that the steel bar had penetrated the cervical spinal canal at the C6–7 level,causing C6 and C7 vertebral body fracture,C6 left lamina fracture,left facet joint fracture,and penetration of the cervical spinal cord.The steel bar was successfully removed through an open surgical procedure by a multidisciplinary team.During the surgery,we found that the cervical vertebra,cervical spinal canal and cervical spinal cord were all severely injured.Postoperative CT demonstrated severe penetration of the cervical spinal canal but the patient returned to a fully functional level without any neurological deficits.CONCLUSION Even with a serious cervical spinal canal penetrating trauma,the patient could resume normal work and life after appropriate treatment.

Exploiting fly models to investigate rare human neurological disorders

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.

Neurological Disorders Caused by Structural Dysfunction of VANGL2

Background: VANGL2 plays a variety of roles in various cellular processes, including tissue morphogenesis, asymmetric cell division, and nervous system development. There is currently a lack of systematic organization in the development and disease of the nervous system. Purpose: To explore the role of VANGL2 in the development of the nervous system and related diseases. Methods: Literature review and analysis of the role of VANGL2 in the development and disease of the nervous system. Results: VANGL2 defects lead to the development of the nervous system through the misconfiguration of various cells, which affects the development of the cochlea, the conduction of neural signals, and the development of nervous system-related diseases such as Alzheimer’s disease, GBM, Bohling-Opitz syndrome, and hydrocephalus. Conclusions: The VANGL2 gene is essential for nervous system development and its deficiency is linked to severe congenital conditions and various disorders, highlighting the need for more research on treatments for related gene defects.

Subarachnoid hemorrhage misdiagnosed as acute coronary syndrome leading to catastrophic neurologic injury: A case report

BACKGROUND Elevated levels of cardiac troponin and abnormal electrocardiogram changes are the primary basis for clinical diagnosis of acute coronary syndrome(ACS).Troponin levels in ACS patients can often be more than 50 times the upper reference limit.Some patients with subarachnoid hemorrhage(SAH)also show electrocardiogram abnormalities,myocardial damage,and elevated cardiac biomarkers.Unlike ACS patients,patients with SAH only have a slight increase in troponin,and the use of anticoagulants or antiplatelet drugs is prohibited.Because of the opposite treatment modalities,it is essential for clinicians to distinguish between SAH and ACS.CASE SUMMARY A 56-year-old female patient was admitted to the emergency department at night with a sudden onset of severe back pain.The final diagnosis was intraspinal hematoma in the thoracic spine.We performed an emergency thoracic spinal canal hematoma evacuation procedure with the assistance of a microscope.Intraoperatively,diffuse hematoma formation was found in the T7-T10 spinal canal,and no obvious spinal vascular malformation changes were observed.Postoperative head and spinal magnetic resonance imaging(MRI)showed a small amount of SAH in the skull,no obvious abnormalities in the cervical and thoracic spinal canals,and no abnormal signals in the lumbar spinal canal.Thoracoab-dominal aorta computed tomography angiography showed no vascular malfor-mation.Postoperative motor system examination showed Medical Research Council Scale grade 1/5 strength in both lower extremities,and the patient experienced decreased sensation below the T12 rib margin and reported a Visual Analog Scale score of 3.CONCLUSION Extremely elevated troponin levels(more than 50 times the normal range)are not unique to coronary artery disease.SAH can also result in extremely high troponin levels,and antiplatelet drugs are contraindicated in such cases.Emergency MRI can help in the early differential diagnosis,as a misdiagnosis of ACS can lead to catastrophic neurological damage in patients with spontaneous spinal SAH.

Application prospects of urine-derived stem cells in neurological and musculoskeletal diseases

Urine-derived stem cells(USCs)are derived from urine and harbor the potential of proliferation and multidirectional differentiation.Moreover,USCs could be reprogrammed into pluripotent stem cells[namely urine-derived induced pluripotent stem cells(UiPSCs)]through transcription factors,such as octamer binding transcription factor 4,sex determining region Y-box 2,kruppel-like factor 4,myelocytomatosis oncogene,and Nanog homeobox and protein lin-28,in which the first four are known as Yamanaka factors.Mounting evidence supports that USCs and UiPSCs possess high potential of neurogenic,myogenic,and osteogenic differentiation,indicating that they may play a crucial role in the treatment of neurological and musculoskeletal diseases.Therefore,we summarized the origin and physiological characteristics of USCs and UiPSCs and their therapeutic application in neurological and musculoskeletal disorders in this review,which not only contributes to deepen our understanding of hallmarks of USCs and UiPSCs but also provides the theoretical basis for the treatment of neurological and musculoskeletal disorders with USCs and UiPSCs.

Application of Enzyme Inhibition Therapy in the Management/Treatment of Neurological Conditions, Diseases, and Disorders

Enzyme inhibition therapy uses specific molecules to inhibit enzyme activity, targeting disease-related enzymes in medical treatments like cancer treatment and infectious disease management. Different types of inhibitors, competitive and non-competitive, bind to different sites and alter enzyme function. The success of this therapy depends on the inhibitor’s specificity and delivery to the target site. Further research could lead to more effective treatments. Nowadays, the majority of medications are enzyme inhibitors and are in the clinical or pre-clinical stages of drug development. Enzyme inhibitors are often prescribed medications for a variety of illnesses, including neurological problems. There is only symptomatic therapy available for many neurological conditions, particularly neuro-degenerative disorders, as opposed to therapy based on knowledge of the underlying mechanisms of these diseases. Enzyme inhibitors are useful as they block the function of certain enzymes whose aberrant activity could be contributing to the illness. They also alleviate the symptoms and stop the disease’s progression. This review discusses the mechanism of action of several enzyme inhibitors that have been prescribed as medications for neurological illnesses as well as some that are still in research stages.

The Effect of Different Hyperbaric Oxygen Treatment Time Windows on Neurological Function and Prognosis in Acute Cerebral Infarction

Objective:To observe the effects of different hyperbaric oxygen treatment time windows on the prognosis and neurological function of acute cerebral infarction.Method:160 patients with acute cerebral infarction admitted to Xiangyang Central Hospital in Hubei Province were randomly divided into four groups,each with 40 cases,using a random number table method.According to the 2017 guidelines for the treatment of cerebral infarction,the control group received routine treatment for acute cerebral infarction;On the basis of the control group,patients in Group A received hyperbaric oxygen therapy within 48 hours of onset;Group B patients receive hyperbaric oxygen therapy within 3-6 days of onset;Group C patients receive hyperbaric oxygen therapy within 7-12 days of onset.Observe the efficacy,recurrence,and neurological function recovery of four groups of patients after treatment.Result:There was no statistically significant difference in the National Institutes of Health Stroke Scale(NIHSS)and Barthel Index(BI)scores among the four groups before treatment(P>0.05).There were statistically significant differences in NIHSS and BI scores between 14 and 30 days after treatment and before treatment(F=16.352,27.261,11.899,28.326,P<0.05).At 14 and 30 days after treatment,the NIHSS score in Group A decreased compared to the control group,Group B,and Group C,while the BI score increased compared to the control group,Group B,and Group C,with statistical significance(P<0.05).There was no statistically significant difference in NIHSS and BI scores between Group C and the control group after treatment(P>0.05).After 30 days of treatment,the total effective rate of Group A was higher than that of the control group and Group C,and the difference was statistically significant(X2=6.135,P<0.05).The one-year recurrence rate of Group A and Group B is lower than that of Group C and the control group,and the difference is statistically significant(X2=8.331,P<0.05).There was no statistically significant difference in adverse reactions among the four groups(P>0.05).Conclusion:Patients with acute cerebral infarction who receive hyperbaric oxygen therapy within 48 hours can improve neurological function and reduce the recurrence rate.The efficacy of receiving hyperbaric oxygen therapy within 7-12 days of onset is equivalent to that of not receiving hyperbaric oxygen therapy.

Repetitive transcranial magnetic stimulation promotes neurological functional recovery in rats with traumatic brain injury by upregulating synaptic plasticity-related proteins

Studies have shown that repetitive transcra nial magnetic stimulation(rTMS)can enhance synaptic plasticity and improve neurological dysfunction.Howeve r,the mechanism through which rTMS can improve moderate traumatic brain injury remains poorly understood.In this study,we established rat models of moderate traumatic brain injury using Feeney's weight-dropping method and treated them using rTMS.To help determine the mechanism of action,we measured levels of seve ral impo rtant brain activity-related proteins and their mRNA.On the injured side of the brain,we found that rTMS increased the protein levels and mRNA expression of brain-derived neurotrophic factor,tropomyosin receptor kinase B,N-methyl-D-aspartic acid receptor 1,and phosphorylated cAMP response element binding protein,which are closely associated with the occurrence of long-term potentiation.rTMS also partially reve rsed the loss of synaptophysin after injury and promoted the remodeling of synaptic ultrastructure.These findings suggest that upregulation of synaptic plasticity-related protein expression is the mechanism through which rTMS promotes neurological function recovery after moderate traumatic brain injury.

Augmentation of transforming growth factor-βsignaling for the treatment of neurological disorders

Members of the transforming growth factor-β(TGF-β)superfamily perform a wide range of essential functions during development and in adulthood,as well as in response to injury and inflammation(Luo,2022).In the adult central nervous system,TGF-βs and their receptors are widely expressed in all of the major neuronal,glial,and vascular cell types.Members of the TGF-βsuperfamily are pivotal responders to pathological insults to the brain.Dysfunction of TGF-βsignaling contributes to pathogenesis of neurological disorders.Manipulation of TGF-βsignaling pathway alters pathological and functional outcomes in models of neurological diseases(Luo,2022).Therefore,the TGF-βsignaling pathway has emerged as a potential therapeutic target against neurological diseases.

Neuro faces of beneficial T cells:essential in brain,impaired in aging and neurological diseases,and activated functionally by neurotransmitters and neuropeptides

T cells are essential for a healthy life,performing continuously:immune surveillance,recognition,protection,activation,suppression,assistance,eradication,secretion,adhesion,migration,homing,communications,and additional tasks.This paper describes five aspects of normal beneficial T cells in the healthy or diseased brain.First,normal beneficial T cells are essential for normal healthy brain functions:cognition,spatial learning,memory,adult neurogenesis,and neuroprotection.T cells decrease secondary neuronal degeneration,increase neuronal survival after central nervous system(CNS) injury,and limit CNS inflammation and damage upon injury and infection.Second,while pathogenic T cells contribute to CNS disorders,recent studies,mostly in animal models,show that specific subpopulations of normal beneficial T cells have protective and regenerative effects in seve ral neuroinflammatory and neurodegenerative diseases.These include M ultiple Sclerosis(MS),Alzheimer’s disease,Parkinson’s disease,Amyotrophic Lateral Sclerosis(ALS),stro ke,CNS trauma,chronic pain,and others.Both T cell-secreted molecules and direct cell-cell contacts deliver T cell neuroprotective,neuro regenerative and immunomodulato ry effects.Third,normal beneficial T cells are abnormal,impaired,and dysfunctional in aging and multiple neurological diseases.Different T cell impairments are evident in aging,brain tumors(mainly Glioblastoma),seve re viral infections(including COVID-19),chro nic stress,major depression,schizophrenia,Parkinson’s disease,Alzheimer’s disease,ALS,MS,stro ke,and other neuro-pathologies.The main detrimental mechanisms that impair T cell function are activation-induced cell death,exhaustion,senescence,and impaired T cell stemness.Fo urth,several physiological neurotransmitters and neuro peptides induce by themselves multiple direct,potent,beneficial,and therapeutically-relevant effects on normal human T cells,via their receptors in T cells.This scientific field is called "Nerve-Driven Immunity".The main neurotransmitters and neuropeptides that induce directly activating and beneficial effects on naive normal human T cells are:dopamine,glutamate,GnRH-Ⅱ,neuropeptide Y,calcitonin gene-related peptide,and somatostatin.Fifth, "Personalized Adoptive Neuro-Immunotherapy".This is a novel unique cellular immunotherapy,based on the "Nerve-Driven Immunity" findings,which was recently designed and patented for safe and repeated rejuvenation,activation,and improvement of impaired and dysfunctional T cells of any person in need,by ex vivo exposure of the person’s T cells to neurotransmitters and neuropeptides.Personalized adoptive neuro-immunotherapy includes an early ex vivo personalized diagnosis,and subsequent ex vivo in vivo personalized adoptive therapy,tailo red according to the diagnosis.The Personalized Adoptive Neuro-Immunotherapy has not yet been tested in humans,pending validation of safety and efficacy in clinical trials,especially in brain tumors,chronic infectious diseases,and aging,in which T cells are exhausted and/or senescent and dysfunctional.

Erythropoietin inhibits ferroptosis and ameliorates neurological function after spinal cord injury

Ferroptosis is one of the critical pathological events in spinal cord injury.Erythropoietin has been reported to improve the recovery of spinal cord injury.However,whether ferroptosis is involved in the neuroprotective effects of erythropoietin on spinal cord injury has not been examined.In this study,we established rat models of spinal cord injury by modified Allen’s method and intraperitoneally administered 1000 and 5000 IU/kg erythropoietin once a week for 2 successive weeks.Both low and high doses of erythropoietin promoted recovery of hindlimb function,and the high dose of erythropoietin led to better outcome.High dose of erythropoietin exhibited a stronger suppressive effect on ferroptosis relative to the low dose of erythropoietin.The effects of erythropoietin on inhibiting ferroptosis-related protein expression and restoring mitochondrial morphology were similar to those of Fer-1(a ferroptosis suppressor),and the effects of erythropoietin were largely diminished by RSL3(ferroptosis activator).In vitro experiments showed that erythropoietin inhibited RSL3-induced ferroptosis in PC12 cells and increased the expression of xCT and Gpx4.This suggests that xCT and Gpx4 are involved in the neuroprotective effects of erythropoietin on spinal cord injury.Our findings reveal the underlying anti-ferroptosis role of erythropoietin and provide a potential therapeutic strategy for treating spinal cord injury.

Repurposing niclosamide for the treatment of neurological disorders

Neurological disorders are still one of the major causes of death,and the vast need to find efficacious therapy is nowadays an essential goal of the scientific community.For Parkinson's disease(PD),amyotrophic lateral sclerosis(ALS),spinal cord injury,and intracerebral hemorrhage.

Humanization for neurological disease modeling:A roadmap to increase the potential of Drosophila model systems

Neuroscience and neurology research is dominated by experimentation with rodents.Around 75%of neurology disease-associated genes have orthologs in Drosophila mel-anogaster,the fruit fly amenable to complex neurological and behavioral investiga-tions.However,non-vertebrate models including Drosophila have so far been unable to significantly replace mice and rats in this field of studies.One reason for this situ-ation is the predominance of gene overexpression(and gene loss-of-function)meth-odologies used when establishing a Drosophila model of a given neurological disease,a strategy that does not recapitulate accurately enough the genetic disease condi-tions.I argue here the need for a systematic humanization approach,whereby the Drosophila orthologs of human disease genes are replaced with the human sequences.This approach will identify the list of diseases and the underlying genes that can be adequately modeled in the fruit fly.I discuss the neurological disease genes to which this systematic humanization approach should be applied and provide an example of such an application,and consider its importance for subsequent disease modeling and drug discovery in Drosophila.I argue that this paradigm will not only advance our un-derstanding of the molecular etiology of a number of neurological disorders,but will also gradually enable researchers to reduce experimentation using rodent models of multiple neurological diseases and eventually replace these models.