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1.
Artigo em Russo | MEDLINE | ID: mdl-33834727

RESUMO

Progressive supranuclear palsy (PNP) is a neurodegenerative disease characterized by a combination of progressive akinetic-rigid syndrome, postural instability with frequent falls, supranuclear ophthalmoplegia, pseudobulbar syndrome and frontal dementia. The disease usually develops after the sixth decade of life, and has a progressive course. An own description of the clinical case of progressive supranuclear palsy in a 79-year-old patient with oromandibular hyperkinesis while taking levodopa is presented.


Assuntos
Discinesias , Transtornos dos Movimentos , Doenças Neurodegenerativas , Paralisia Supranuclear Progressiva , Idoso , Humanos , Levodopa/efeitos adversos , Paralisia Supranuclear Progressiva/induzido quimicamente , Paralisia Supranuclear Progressiva/tratamento farmacológico
2.
Rev Infirm ; 70(269): 24-25, 2021 Mar.
Artigo em Francês | MEDLINE | ID: mdl-33742587

RESUMO

The team of the geriatric department of the Grenoble-Alpes (38) University Hospital Center has created the Accompagner therapeutic education program to meet the needs of patients suffering from neurocognitive disorders in the context of a neurodegenerative disease and their families. Presentation and current organization of the workshops.


Assuntos
Cuidadores , Doenças Neurodegenerativas , Educação de Pacientes como Assunto , Idoso , Cuidadores/educação , França , Hospitais Universitários , Humanos , Doenças Neurodegenerativas/terapia
3.
Life Sci ; 274: 119343, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33716063

RESUMO

Aging is a risk factor for major central nervous system (CNS) disorders. More specifically, aging can be inked to neurodegenerative diseases (NDs) because of its deteriorating impact on neurovascular unit (NVU). Metformin, a first line FDA-approved anti-diabetic drug, has gained increasing interest among researchers for its role in improving aging-related neurodegenerative disorders. Additionally, numerous studies have illustrated metformin's role in ischemic stroke, a cerebrovascular disorder in which the NVU becomes dysfunctional which can lead to permanent life-threatening disabilities. Considering metformin's beneficial preclinical actions on various disorders, and the drug's role in alleviating severity of these conditions through involvement in commonly characterized cellular pathways, we discuss the potential of metformin as a suitable drug candidate for repurposing in CNS disorders.


Assuntos
Envelhecimento/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Envelhecimento/patologia , Animais , Isquemia Encefálica/patologia , Humanos , Doenças Neurodegenerativas/patologia , Acidente Vascular Cerebral/patologia
4.
Molecules ; 26(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669787

RESUMO

Despite the improvements in life expectancy, neurodegenerative conditions have arguably become the most dreaded maladies of older people. The neuroprotective and anti-ageing potentials of essential oils (EOs) are widely evaluated around the globe. The objective of this review is to analyse the effectiveness of EOs as neuroprotective remedies among the four common age-related neurodegenerative diseases. The literature was extracted from three databases (PubMed, Web of Science and Google Scholar) between the years of 2010 to 2020 using the medical subject heading (MeSH) terms "essential oil", crossed with "Alzheimer's disease (AD)", "Huntington's disease (HD)", "Parkinson's disease (PD)" or "amyotrophic lateral sclerosis (ALS)". Eighty three percent (83%) of the studies were focused on AD, while another 12% focused on PD. No classifiable study was recorded on HD or ALS. EO from Salvia officinalis has been recorded as one of the most effective acetylcholinesterase and butyrylcholinesterase inhibitors. However, only Cinnamomum sp. has been assessed for its effectiveness in both AD and PD. Our review provided useful evidence on EOs as potential neuroprotective remedies for age-related neurodegenerative diseases.


Assuntos
Envelhecimento/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Neuroproteção , Fármacos Neuroprotetores/uso terapêutico , Óleos Voláteis/uso terapêutico , Humanos , Publicações
5.
Molecules ; 26(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670164

RESUMO

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1ß and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1ß and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.


Assuntos
Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Neurodegenerativas/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Doenças Neurodegenerativas/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transdução de Sinais/genética
6.
Adv Exp Med Biol ; 1286: 213-223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33725356

RESUMO

Age-related neurodegenerative diseases have detrimental consequences on health of many patients and result in mortality. The current treatment options are limited and usually fail to correct the underlying pathology. AAV-based gene therapies have proved to be safe based on the data available on clinical trials for several monogenic diseases. Therefore, such therapies can pave the way to treat neurodegenerative diseases likes Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Here, the advantages of AAV-based gene therapies are discussed with emphasis on efforts of developing novel capsids with superior therapeutic efficacy. Furthermore, the results of clinical trials on AD, PD, and ALS are summarized.


Assuntos
Doença de Alzheimer , Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Doença de Parkinson , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/terapia , Terapia Genética , Humanos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , Doença de Parkinson/genética , Doença de Parkinson/terapia
7.
Adv Exp Med Biol ; 1286: 251-264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33725358

RESUMO

Psychiatric and neurodegenerative disorders such as schizophrenia (SCZ), Parkinson's disease (PD), and Alzheimer's disease (AD) continue to grow around the world with a high impact on health, social, and economic outcomes for the patient and society. Despite efforts, the etiology and pathophysiology of these disorders remain unclear. Omics technologies have contributed to the understanding of the molecular mechanisms that underlie these complex disorders and have suggested novel potential targets for treatment and diagnostics. Here, we have highlighted the unique and common pathways shared between SCZ, PD, and AD and highlight the main proteomic findings over the last 5 years using in vitro models, postmortem brain samples, and cerebrospinal fluid (CSF) or blood of patients. These studies have identified possible therapeutic targets and disease biomarkers. Further studies including target validation, the use of large sample sizes, and the integration of omics findings with bioinformatics tools are required to provide a better comprehension of pharmacological targets.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Biomarcadores , Humanos , Doenças Neurodegenerativas/genética , Proteômica
8.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670394

RESUMO

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global challenge. Currently, there is some information on the consequences of COVID-19 infection in multiple sclerosis (MS) patients, as it is a newly discovered coronavirus, but its far-reaching effects on participation in neurodegenerative diseases seem to be significant. Recent cases reports showed that SARS-CoV-2 may be responsible for initiating the demyelination process in people who previously had no symptoms associated with any nervous system disorders. It is presently known that infection of SARS-CoV-2 evokes cytokine storm syndrome, which may be one of the factors leading to the acute cerebrovascular disease. One of the substantial problems is the coexistence of cerebrovascular disease and MS in an individual's life span. Epidemiological studies showed an enhanced risk of death rate from vascular disabilities in MS patients of approximately 30%. It has been demonstrated that patients with severe SARS-CoV-2 infection usually show increased levels of D-dimer, fibrinogen, C-reactive protein (CRP), and overactivation of blood platelets, which are essential elements of prothrombotic events. In this review, the latest knowledge gathered during an ongoing pandemic of SARS-CoV-2 infection on the neurodegeneration processes in MS is discussed.


Assuntos
/complicações , Esclerose Múltipla/complicações , Doenças Neurodegenerativas/etiologia , Animais , /virologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Humanos , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/virologia , Trombose/etiologia , Trombose/patologia
9.
Adv Pharmacol ; 90: 277-306, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33706937

RESUMO

Neurodegenerative diseases (NDDs) are in need of new drug discovery approaches. Our previous systematic analyses of Huntington's Disease (HD) literature for protein-protein interactors (PPIs) and modifiers of mutant Huntingtin-driven phenotypes revealed enrichment for PPIs of genes required for homeostatic synaptic plasticity (HSP) and exosome (EV) function and exosomal proteins, which in turn highly overlapped each other and with PPIs of genes associated with other NDDs. We proposed that HSP and EVs are linked to each other and are also involved in NDD pathophysiology. Recent studies showed that HSP is indeed altered in HD and AD, and that presynaptic homeostatic plasticity in motoneurons compensates for ALS pathology. Eliminating it causes earlier degeneration and death. If this holds true in other NDDs, drug discovery in animal models should then include elucidation of homeostatic compensation that either masks phenotypes of physiologically expressed mutant genes or are overridden by their overexpression. In this new conceptual framework, enhancing such underlying homeostatic compensation forms the basis for novel therapeutic strategies to slow progression of NDDs. Moreover, if EVs are linked to HSP, then their ability to penetrate the brain, target cell types, deliver miRNA and other molecules can be leveraged to develop attractive drug modalities. Testing this new framework is posed as four questions on model development and mechanistic studies progressing from higher throughput platforms to mouse models. Similar approaches may apply to other CNS disorders including schizophrenia, autism, Rett and Fragile X syndromes due to potential links of their susceptibility genes to HSP and EVs.


Assuntos
Descoberta de Drogas , Exossomos/metabolismo , Homeostase , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo
10.
No Shinkei Geka ; 49(2): 419-424, 2021 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-33762467

RESUMO

Neuronal intranuclear inclusion disease(NIID)is a progressive neurodegenerative condition characterized by eosinophilic hyaline intranuclear inclusions in neuronal and other somatic cells. Since 2011, when skin biopsy was proven to be a diagnostic tool, the incidence of NIID has been increasing. Its symptoms include dementia, muscle weakness, and sensory or autonomic disturbance. MRI shows hyperintense lesions of the subcortical white matter, especially on the U-fiber. These findings persist and continue to worsen for years.


Assuntos
Corpos de Inclusão Intranuclear , Doenças Neurodegenerativas , Biópsia , Humanos , Imagem por Ressonância Magnética , Doenças Neurodegenerativas/diagnóstico por imagem
11.
Arq Neuropsiquiatr ; 79(2): 127-132, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33759979

RESUMO

BACKGROUND: Spinal muscular atrophy (SMA) is a neurodegenerative disease of lower motor neurons associated with frequent occurrence of spinal deformity. Nusinersen is an antisense oligonucleotide that increases SMN protein level and is administrated by frequent intrathecal lumbar injections. Thus, spinal deformities and previous spinal surgery are important challenges for drug delivery in SMA. OBJECTIVE: To report imaging methods used for Nusinersen injection in SMA patients. METHODS: Nusinersen injection procedures in SMA types 2 and 3 patients who had previous spinal surgery were analyzed retrospectively to describe the imaging and puncture procedures, as well as the occurrence of complications. RESULTS: Nine SMA patients (14 to 50 years old) underwent 57 lumbar punctures for nusinersen injection. Six patients had no interlaminar space available; in five of them, a transforaminal approach was used, and another one underwent a surgery to open a posterior bone window for the injections. Transforaminal puncture was performed using CT scan in three cases and fluoroscopy in the other two, with a similar success rate. One patient in the transforaminal group had post-procedure radiculitis, and another one had vagal reaction (hypotension). In three cases, with preserved interlaminar space, injections were performed by posterior interlaminar puncture, and only one adverse event was reported (post-puncture headache). CONCLUSION: In SMA patients with previous spinal surgery, the use of imaging-guided intervention is necessary for administering intrathecal nusinersen. Transforaminal technique is indicated in patients for whom the interlaminar space is not available, and injections should always be guided by either CT or fluoroscopy.


Assuntos
Atrofia Muscular Espinal , Doenças Neurodegenerativas , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos , Estudos Retrospectivos , Adulto Jovem
12.
Nihon Yakurigaku Zasshi ; 156(2): 66-70, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33642532

RESUMO

Neurons communicate with other cells via long processes, i.e., axons and dendrites, functionally and morphologically specialized tree-like structures. Formation and maintenance of such processes play a crucial role in neuronal functions. Axons are particularly important for construction of neuronal network, and, together with synapses at the end of them, play a central role in transmission of information. Axonal degeneration, a phenomenon that once formed axons lose structural integrity, is most typically observed as "Wallerian degeneration", in which injured axonal segment (distal to the site of injury) degenerates. Different forms of axonal degeneration are also observed in a variety of contexts, including pathogenesis and progression of different neurodegenerative disorders, as well as neuronal network formation during development. Thus, understanding of regulatory mechanism of axonal degeneration is important in many aspects, such as for clarification of neuronal morphogenesis mechanism, and for development of neuroprotective therapy against neurological disorders. Here, I discuss recent progress in the research field of axonal degeneration mechanism.


Assuntos
Doenças Neurodegenerativas , Degeneração Walleriana , Axônios , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios , Sinapses , Degeneração Walleriana/tratamento farmacológico , Degeneração Walleriana/patologia
13.
Nihon Yakurigaku Zasshi ; 156(2): 76-80, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33642534

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disease with motor symptoms, such as tremor, akinesia/bradykinesia, rigidity and postural instability due to a loss of nigrostriatal dopaminergic neurons; PD patients also exhibit non-motor symptoms, such as hyposmia, orthostatic hypotension and constipation, which precede motor symptoms. Pathologically, Lewy bodies and neurites, which contains α-synuclein, are observed in the central and peripheral nervous system. To date, it is hypothesized that PD pathology appears first in the olfactory bulb and the enteric nervous system, and propagates progressively through the substantia nigra to finally reach the cerebral cortex. Major medications at present are nosotropic treatments to improve motor dysfunction in PD. Therefore, development of disease-modifying drug is required to slow or prevent PD progression. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects by production of antioxidants and neurotrophic factors and clearing toxic molecules. In the previous study, we demonstrated that astrocytes produced antioxidative molecules metallothionein (MT)-1/2 in response to oxidative stress and protected dopaminergic neurons against oxidative stress. MTs are cysteine-rich proteins possessing antioxidative properties. MTs bind to metals such as zinc (Zn) and copper (Cu) and function in metal homeostasis and detoxification; MTs regulate Zn-mediated transcriptional activation of various genes. Recently, it is reported that MTs prevent Cu-induced aggregation of α-synuclein. In this article, we review a new therapeutic strategy of neuroprotection in PD by targeting MTs in astrocytes.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Astrócitos , Proteínas de Transporte , Humanos , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína
14.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(2): 189-194, 2021 Feb 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33678657

RESUMO

Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Atividades Cotidianas , Doença de Alzheimer/genética , Humanos , Mutação , Presenilina-1/genética , Presenilina-2/genética
15.
Nat Commun ; 12(1): 1484, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674585

RESUMO

Mechanical stimuli initiate adaptive signal transduction pathways, yet exceeding the cellular capacity to withstand physical stress results in death. The molecular mechanisms underlying trauma-induced degeneration remain unclear. In the nematode C. elegans, we have developed a method to study cellular degeneration in response to mechanical stress caused by blunt force trauma. Herein, we report that physical injury activates the c-Jun kinase, KGB-1, which modulates response elements through the AP-1 transcriptional complex. Among these, we have identified a dual-specificity MAPK phosphatase, VHP-1, as a stress-inducible modulator of neurodegeneration. VHP-1 regulates the transcriptional response to mechanical stress and is itself attenuated by KGB-1-mediated inactivation of a deubiquitinase, MATH-33, and proteasomal degradation. Together, we describe an uncharacterized stress response pathway in C. elegans and identify transcriptional and post-translational components comprising a feedback loop on Jun kinase and phosphatase activity.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Fosfatases de Especificidade Dupla/metabolismo , Estresse Mecânico , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Fosfatases de Especificidade Dupla/genética , Endopeptidases/metabolismo , Técnicas de Silenciamento de Genes , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Doenças Neurodegenerativas/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Transcriptoma
16.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670490

RESUMO

The mitochondrial respiratory chain is the main site of reactive oxygen species (ROS) production in the cell. Although mitochondria possess a powerful antioxidant system, an excess of ROS cannot be completely neutralized and cumulative oxidative damage may lead to decreasing mitochondrial efficiency in energy production, as well as an increasing ROS excess, which is known to cause a critical imbalance in antioxidant/oxidant mechanisms and a "vicious circle" in mitochondrial injury. Due to insufficient energy production, chronic exposure to ROS overproduction consequently leads to the oxidative damage of life-important biomolecules, including nucleic acids, proteins, lipids, and amino acids, among others. Different forms of mitochondrial dysfunction (mitochondriopathies) may affect the brain, heart, peripheral nervous and endocrine systems, eyes, ears, gut, and kidney, among other organs. Consequently, mitochondriopathies have been proposed as an attractive diagnostic target to be investigated in any patient with unexplained progressive multisystem disorder. This review article highlights the pathomechanisms of mitochondriopathies, details advanced analytical tools, and suggests predictive approaches, targeted prevention and personalization of medical services as instrumental for the overall management of mitochondriopathy-related cascading pathologies.


Assuntos
Metabolismo Energético , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Estresse Oxidativo , Animais , Carcinogênese/patologia , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Medicina de Precisão , Espécies Reativas de Oxigênio/metabolismo
17.
Mol Pharmacol ; 99(4): 256-265, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33547249

RESUMO

The high failure rate of drugs in the clinical pipeline is likely in part the result of inadequate preclinical models, particularly those for neurologic disorders and neurodegenerative disease. Such preclinical animal models often suffer from fundamental species differences and rarely recapitulate all facets of neurologic conditions, whereas conventional two-dimensional (2D) in vitro models fail to capture the three-dimensional spatial organization and cell-to-cell interactions of brain tissue that are presumed to be critical to the function of the central nervous system. Recent studies have suggested that stem cell-derived neuronal organoids are more physiologically relevant than 2D neuronal cultures because of their cytoarchitecture, electrophysiological properties, human origin, and gene expression. Hence there is interest in incorporating such physiologically relevant models into compound screening and lead optimization efforts within drug discovery. However, despite their perceived relevance, compared with previously used preclinical models, little is known regarding their predictive value. In fact, some have been wary to broadly adopt organoid technology for drug discovery because of the low-throughput and tedious generation protocols, inherent variability, and lack of compatible moderate-to-high-throughput screening assays. Consequently, microfluidic platforms, specialized bioreactors, and automated assays have been and are being developed to address these deficits. This mini review provides an overview of the gaps to broader implementation of neuronal organoids in a drug discovery setting as well as emerging technologies that may better enable their utilization. SIGNIFICANCE STATEMENT: Neuronal organoid models offer the potential for a more physiological system in which to study neurological diseases, and efforts are being made to employ them not only in mechanistic studies but also in profiling/screening purposes within drug discovery. In addition to exploring the utility of neuronal organoid models within this context, efforts in the field aim to standardize such models for consistency and adaptation to screening platforms for throughput evaluation. This review covers potential impact of and hurdles to implementation.


Assuntos
Descoberta de Drogas/métodos , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Organoides/efeitos dos fármacos , Organoides/fisiologia , Animais , Descoberta de Drogas/tendências , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Doenças Neurodegenerativas/fisiopatologia
18.
Nat Neurosci ; 24(3): 331-342, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33619405

RESUMO

Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling.


Assuntos
Diferenciação Celular/fisiologia , Metilação de DNA/fisiologia , Células-Tronco Pluripotentes Induzidas/citologia , Organoides/citologia , Redes Reguladoras de Genes , Humanos , Técnicas In Vitro , Doenças Neurodegenerativas/genética
19.
Nat Neurosci ; 24(3): 297-311, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33526943

RESUMO

Gene therapy is making a comeback. With its twin promise of targeting disease etiology and 'long-term correction', gene-based therapies (defined here as all forms of genome manipulation) are particularly appealing for neurodegenerative diseases, for which conventional pharmacologic approaches have been largely disappointing. The recent success of a viral-vector-based gene therapy in spinal muscular atrophy-promoting survival and motor function with a single intravenous injection-offers a paradigm for such therapeutic intervention and a platform to build on. Although challenges remain, the newfound optimism largely stems from advances in the development of viral vectors that can diffusely deliver genes throughout the CNS, as well as genome-engineering tools that can manipulate disease pathways in ways that were previously impossible. Surely spinal muscular atrophy cannot be the only neurodegenerative disease amenable to gene therapy, and one can imagine a future in which the toolkit of a clinician will include gene-based therapeutics. The goal of this Review is to highlight advances in the development and application of gene-based therapies for neurodegenerative diseases and offer a prospective look into this emerging arena.


Assuntos
Terapia Genética , Doenças Neurodegenerativas/terapia , Animais , Humanos , Doenças Neurodegenerativas/genética
20.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540859

RESUMO

One of the essential functions of microglia is to continuously sense changes in their environment and adapt to those changes. For this purpose, they use a set of genes termed the sensome. This sensome is comprised of the most abundantly expressed receptors on the surface of microglia. In this study, we updated previously identified mouse microglial sensome by incorporating an additional published RNAseq dataset into the data-analysis pipeline. We also identified members of the human microglial sensome using two independent human microglia RNAseq data sources. Using both the mouse and human microglia sensomes, we identified a key set of genes conserved between the mouse and human microglial sensomes as well as some differences between the species. We found a key set of 57 genes to be conserved in both mouse and human microglial sensomes. We define these genes as the "microglia core sensome". We then analyzed expression of genes in this core sensome in five different datasets from two neurodegenerative disease models at various stages of the diseases and found that, overall, changes in the level of expression of microglial sensome genes are specific to the disease or condition studied. Our results highlight the relevance of data generated in mice for understanding the biology of human microglia, but also stress the importance of species-specific gene sets for the investigation of diseases involving microglia. Defining this microglial specific core sensome may help identify pathological changes in microglia in humans and mouse models of human disease.


Assuntos
Microglia/metabolismo , Receptores de Superfície Celular/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Córtex Cerebral/metabolismo , Conjuntos de Dados como Assunto , Expressão Gênica , Ontologia Genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA-Seq , Receptores de Superfície Celular/análise , Especificidade da Espécie
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