RESUMO
Background: For the past five years, our annual reports have been tracking the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD). These reviews have followed the progress both of "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease-modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Efforts have also been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. Methods: A dataset of clinical trials for drug therapies in PD using trial data downloaded from the ClinicalTrials.gov online registry was generated. A breakdown analysis of all the studies that were active as of January 31st, 2024, was conducted. This analysis involved categorizing the trials based on both the mechanism of action (MOA) and the drug target. Results: There were 136 active Phase 1-3 trials evaluating drug therapies for PD registered on ClinicalTrials.gov, as of January 31, 2024. Of these trials, 76 (56%) were classified as ST trials and 60 (44%) were designated DMT. More than half (58%) of the trials were in Phase 2 testing stage, followed by Phase 1 (30%) and Phase 3 (12%). 35 of the trials were registered since our last report, with the remaining 101 trials appearing in at least one earlier report. Conclusions: The drug development pipeline for PD remains in a robust state with a wide variety of approaches being developed and evaluated in Phase 1 and 2. Yet again, however, only a limited number of DMTs are transitioning to Phase 3.
The development of new medical therapies, particularly for neurodegenerative conditions, is a long process that involves multiple phases of testing before a treatment is approved for use in a doctor's clinic. The first phase assesses the short-term safety of a drug most often in healthy volunteers but sometimes in people affected by the disease. The second phase explores the short-term safety and preliminary efficacy of the agent in people affected by the disease of interest, and the third phase investigates long-term safety and efficacy in a large group of people affected by the disease. For a disease like Parkinson's disease, where the causes of the condition are not well understood, drugs targeting different biological pathways need to be tested to determine which ones may be useful in treating the symptoms, and which could be administered to slow down or stop the progression of the condition. Here, we provide an annual report on the current landscape of both these clinical testing efforts. In total, we reviewed 136 active studies evaluating therapies for Parkinson's disease registered on a clinical trial database called 'ClinicalTrials.gov'. Of these trials, approximately 55% were testing experimental symptomatic treatments, while the rest were focused on slowing down disease progression. More than half (58%) of the studies were in the second phase of clinical testing (short-term safety and preliminary efficacy), but only three studies were found to be testing treatments to stop the progression of Parkinson's in the Phase 3 testing. We concluded that the drug development pipeline for Parkinson's is robust, but more progress needs to be made with late-stage testing of treatments to slow the disease.
Assuntos
Antiparkinsonianos , Ensaios Clínicos como Assunto , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêuticoRESUMO
In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.
Assuntos
Ensaios Clínicos como Assunto , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêuticoRESUMO
BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).
Assuntos
Antiparkinsonianos , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Doença de Parkinson , Peptídeos , Humanos , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Pessoas com Deficiência , Método Duplo-Cego , Transtornos Motores/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/uso terapêutico , Resultado do Tratamento , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Progressão da Doença , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Injeções SubcutâneasRESUMO
BACKGROUND: Since 2020, annual reports on the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) have been generated. These reviews have followed the progress of both "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Additional efforts have been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. METHODS: A dataset of clinical trials for drug therapies in PD was obtained using trial data downloaded from the ClinicalTrials.gov online registry. A breakdown analysis of all the studies that were active as of January 31st, 2023, was conducted. RESULTS: There was a total of 139 clinical trials registered on the ClinicalTrials.gov website as active (with 35 trials newly registered since our last report). Of these trials, 76 (55%) were considered ST and 63 (45%) were designated DMT. Similar to previous years, approximately a third of the studies were in Phase 1 (nâ=â47; 34%), half (nâ=â72, 52%) were in Phase 2 and there were 20 (14%) studies in Phase 3. Novel therapies again represented the most dominant group of experimental treatments in this year's report with 58 (42%) trials testing new agents. Repurposed drugs are present in a third (nâ=â49, 35%) of trials, with reformulations and new claims representing 19% and 4% of studies, respectively. CONCLUSIONS: Our fourth annual review of active clinical trials evaluating ST and DMT therapeutics for PD demonstrates that the drug development pipeline is dynamic and evolving. The slow progress and lack of agents transitioning from Phase 2 to Phase 3 is concerning, but collective efforts by various stakeholders are being made to accelerate the clinical trial process, with the aim of bringing new therapies to the PD community sooner.
Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológicoRESUMO
BACKGROUND: As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) in 2021. This progress included both "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD), which can be categorised further based on their mechanisms of action and class of drug. OBJECTIVE: This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT - in clinical trials for PD during 2021- 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community. METHODS: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. RESULTS: There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%). CONCLUSION: Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute.
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Desenvolvimento de Medicamentos , Doença de Parkinson , COVID-19 , Ensaios Clínicos como Assunto , Humanos , Pandemias , Doença de Parkinson/tratamento farmacológicoRESUMO
A recent breakthrough paper published in Science Translational Medicine has provided compelling evidence that inhibition of Parkin Interacting Substrate (PARIS) may offer clinical researchers an important new therapeutic approach since it shows considerable promise as an important biological target potentially capable of pharmaceutical intervention to slow long term neurodegeneration in patients with Parkinson's disease (PD). We present several PD-relevant perspectives on this paper that were not discussed in that otherwise entirely scientific narrative. We also outline the some of the work leading up to it, including the massive drug screen that proved necessary to discover a clinically suitable inhibitor of PARIS (Farnesol), as well as relevant PD research within the wider drug class, issues surrounding its future formulation, and next steps in translating this new knowledge into the clinic to evaluate possible long-term PD patient benefits.
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Neurônios Dopaminérgicos , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Proteínas Repressoras , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) during 2020. The agents that were investigated can be divided into "symptomatic" (alleviating the features of the condition) and "disease modifying" (attempting to address the underlying biology of PD) treatments, ST and DMT respectively, with further categorisation possible based on mechanism of action and class of therapy. OBJECTIVE: Our goal in this report was to provide an overview of the pharmacological therapies -both ST and DMT - in clinical trials for PD during 2020-2021, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst commercial and academic researchers as well as between the research and patient communities. METHODS: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of February 18th 2021. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. RESULTS: We identified 142 trials on ClinicalTrials.gov and 14 studies on the WHO registries that met our analysis criteria. Of these 156 trials, 91 were ST and 65 were DMT, Of the 145 trials registered on ClinicalTrials.gov in our 2020 analysis, 45 fell off the list and 42 were added. Despite this change, the balance of ST to DMT; the distribution across phases; the profile of therapeutic categories; and the proportion of repurposed therapies (33.5%); all remained very similar. There are only two DMTs in phase 3, and we identified 33 in-between-phase projects. CONCLUSIONS: Despite the effects of the coronavirus pandemic, investment and effort in clinical trials for PD appears to remain strong. There has been little change in the profile of the clinical trial landscape even though, over the past year, there has been considerable change to the content of the list.
Assuntos
Antiparkinsonianos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Desenvolvimento de Medicamentos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , COVID-19 , HumanosRESUMO
The international Linked Clinical Trials (iLCT) program for Parkinson's to date represents one of the most comprehensive drug repurposing programs focused on one disease. Since initial planning in 2010, it has rapidly grown - giving rise to seven completed, and 15 ongoing, clinical trials of 16 agents each aimed at delivering disease modification in Parkinson's disease (PD). In this review, we will provide an overview of the history, structure, process, and progress of the program. We will also present some examples of agents that have been selected and prioritized by the program and subsequently evaluated in clinical trials. Our goal with this review is to provide a template that can be considered across other therapeutic areas.
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BACKGROUND: The majority of current pharmacological treatments for Parkinson's disease (PD) were approved for clinical use in the second half of the last century and they only provide symptomatic relief. Derivatives of these therapies continue to be explored in clinical trials, together with potentially disease modifying therapies that can slow, stop or reverse the condition. OBJECTIVE: To provide an overview of the pharmacological therapies- both symptomatic and disease modifying- currently being clinically evaluated for PD, with the goal of creating greater awareness and opportunities for collaboration amongst commercial and academic researchers as well as between the research and patient communities. METHODS: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov database and performed a breakdown analysis of studies that were active as of January 21, 2020. RESULTS: We identified 145 registered and ongoing clinical trials for therapeutics targeting PD, of which 51 were Phase 1 (35% of the total number of trials), 66 were Phase 2 (46% ), and 28 were Phase 3 (19% ). There were 57 trials (39% ) focused on long-term disease modifying therapies, with the remaining 88 trials (61% ) focused on therapies for symptomatic relief. A total of 50 (34% ) trials were testing repurposed therapies. CONCLUSION: There is a broad pipeline of both symptomatic and disease modifying therapies currently being tested in clinical trials for PD.
Assuntos
Antiparkinsonianos/uso terapêutico , Desenvolvimento de Medicamentos , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Resultado do TratamentoRESUMO
The primary neuropathological characteristics of the Parkinsonian brain are the loss of nigral dopamine neurons and the aggregation of alpha synuclein protein. Efforts to development potentially disease-modifying treatments have largely focused on correcting these aspects of the condition. In the last decade treatments targeting protein aggregation have entered the clinical pipeline. In this chapter we provide an overview of ongoing clinical trial programs for different therapies attempting to reduce protein aggregation pathology in Parkinson's disease. We will also briefly consider various novel approaches being proposed-and being developed preclinically-to inhibit/reduce aggregated protein pathology in Parkinson's.
Assuntos
Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Agregados Proteicos/efeitos dos fármacos , Vacinas/uso terapêutico , alfa-Sinucleína/efeitos dos fármacos , Animais , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologiaRESUMO
The aggregation of alpha-synuclein (α-syn) is a pathological feature of a number of neurodegenerative conditions, including Parkinson's disease. Genetic mutations, abnormal protein synthesis, environmental stress, and aging have all been implicated as causative factors in this process. The importance of water in the polymerisation of monomers, however, has largely been overlooked. In the present study, we highlight the role of hyperosmotic stress in inducing human α-syn to aggregate in cells in vitro, through rapid treatment of the cells with three different osmolytes: sugar, salt and alcohol. This effect is cell-dependent and not due to direct protein-osmolyte interaction, and is specific for α-syn when compared to other neurodegeneration-related proteins, such as Tau or Huntingtin. This new property of α-syn not only highlights a unique aspect of its behaviour which may have some relevance for disease states, but may also be useful as a screening test for compounds to inhibit the aggregation of α-syn in vitro.
Assuntos
Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Benzotiazóis/química , Western Blotting , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Células HEK293 , Temperatura Alta , Humanos , Peróxido de Hidrogênio/farmacologia , L-Lactato Desidrogenase/metabolismo , Camundongos , Concentração Osmolar , Cloreto de Sódio/farmacologia , Dodecilsulfato de Sódio/farmacologia , Ureia/farmacologiaRESUMO
BACKGROUND: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer's disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. OBJECTIVE: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. METHODS: We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. RESULTS: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. CONCLUSION: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.
Assuntos
Doença de Alzheimer/genética , Encéfalo/patologia , Síndrome de Down/complicações , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Linhagem Celular , Progressão da Doença , Exossomos , Feminino , Humanos , Imunidade Inata , Macrófagos/metabolismo , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Fagocitose , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Parkinson's disease (PD) is a progressive neurodegenerative condition that is characterised by the loss of specific populations of neurons in the brain. The mechanisms underlying this selective cell death are unknown but by using laser capture microdissection, the glycoprotein, CD24 has been identified as a potential marker of the populations of cells that are affected in PD. Using in situ hybridization and immunohistochemistry on sections of mouse brain, we confirmed that CD24 is robustly expressed by many of these subsets of cells. To determine if CD24 may have a functional role in PD, we modelled the dopamine cell loss of PD in Cd24 mutant mice using striatal delivery of the neurotoxin 6-OHDA. We found that Cd24 mutant mice have an anatomically normal dopamine system and that this glycoprotein does not modulate the lesion effects of 6-OHDA delivered into the striatum. We then undertook in situ hybridization studies on sections of human brain and found-as in the mouse brain-that CD24 is expressed by many of the subsets of the cells that are vulnerable in PD, but not those of the midbrain dopamine system. Finally, we sought to determine if CD24 is required for the neuroprotective effect of Glial cell-derived neurotrophic factor (GDNF) on the dopaminergic nigrostriatal pathway. Our results indicate that in the absence of CD24, there is a reduction in the protective effects of GDNF on the dopaminergic fibres in the striatum, but no difference in the survival of the cell bodies in the midbrain. While we found no obvious role for CD24 in the normal development and maintenance of the dopaminergic nigrostriatal system in mice, it may have a role in mediating the neuroprotective aspects of GDNF in this system.
Assuntos
Antígeno CD24/genética , Neurônios Dopaminérgicos/fisiologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Antígeno CD24/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Doença de Parkinson/metabolismoRESUMO
Midbrain dopaminergic neurons are highly heterogeneous. They differ in their connectivity and firing patterns and, therefore, in their functional properties. The molecular underpinnings of this heterogeneity are largely unknown, and there is a paucity of markers that distinguish these functional subsets. In this paper, we report the identification and characterization of a novel subset of midbrain dopaminergic neurons located in the ventral tegmental area that expresses the basic helix-loop-helix transcription factor, Neurogenic Differentiation Factor-6 (NEUROD6). Retrograde fluorogold tracing experiments demonstrate that Neurod6+ midbrain dopaminergic neurons neurons project to two distinct septal regions: the dorsal and intermediate region of the lateral septum. Loss-of-function studies in mice demonstrate that Neurod6 and the closely related family member Neurod1 are both specifically required for the survival of this lateral-septum projecting neuronal subset during development. Our findings underscore the complex organization of midbrain dopaminergic neurons and provide an entry point for future studies of the functions of the Neurod6+ subset of midbrain dopaminergic neurons.SIGNIFICANCE STATEMENT Midbrain dopaminergic neurons regulate diverse brain functions, including voluntary movement and cognitive and emotive behaviors. These neurons are heterogeneous, and distinct subsets are thought to regulate different behaviors. However, we currently lack the means to identify and modify gene function in specific subsets of midbrain dopaminergic neurons. In this study, we identify the transcription factor NEUROD6 as a specific marker for a novel subset of midbrain dopaminergic neurons in the ventral midbrain that project to the lateral septum, and we reveal essential roles for Neurod1 and Neurod6 in the survival of these neurons during development. Our findings highlight the molecular and anatomical heterogeneity of midbrain dopaminergic neurons and contribute to a better understanding of this functionally complex group of neurons.
Assuntos
Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Núcleos Septais/citologia , Área Tegmentar Ventral/citologia , Aldeído Desidrogenase/metabolismo , Família Aldeído Desidrogenase 1 , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biotina/análogos & derivados , Biotina/metabolismo , Calbindinas/metabolismo , Contagem de Células , Dextranos/metabolismo , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/genética , Vias Neurais/fisiologia , Fatores de Transcrição Otx/genética , Fatores de Transcrição Otx/metabolismo , Retinal Desidrogenase , Núcleos Septais/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/embriologia , Área Tegmentar Ventral/crescimento & desenvolvimentoRESUMO
Neuroinflammation and activation of innate immunity are early events in neurodegenerative diseases including Alzheimer's disease (AD). Recently, a rare mutation in the gene Triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with a substantial increase in the risk of developing late onset AD. To uncover the molecular mechanisms underlying this association, we investigated the RNA and protein expression of TREM2 in APP/PS1 transgenic mice. Our findings suggest that TREM2 not only plays a critical role in inflammation, but is also involved in neuronal cell survival and in neurogenesis. We have shown that TREM2 is a soluble protein transported by macrophages through ventricle walls and choroid plexus, and then enters the brain parenchyma via radial glial cells. TREM2 protein is essential for neuroplasticity and myelination. During the late stages of life, a lack of TREM2 protein may accelerate aging processes and neuronal cell loss and reduce microglial activity, ultimately leading to neuroinflammation. As inflammation plays a major role in neurodegenerative diseases, a lack of TREM2 could be a missing link between immunomodulation and neuroprotection.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Neuroproteção/fisiologia , Receptores Imunológicos/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/patologia , Células Cultivadas , Humanos , Lipopolissacarídeos , Macrófagos/metabolismo , Macrófagos/patologia , Meninges/metabolismo , Meninges/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Neurogênese/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-DawleyRESUMO
Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.
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Neurônios Dopaminérgicos/citologia , Mesencéfalo/citologia , Mesencéfalo/embriologia , Células-Tronco Neurais/citologia , Neurogênese , Células-Tronco Pluripotentes/citologia , Animais , Linhagem Celular , Técnicas de Reprogramação Celular , Humanos , Aprendizado de Máquina , Mesencéfalo/metabolismo , Camundongos , Neuroglia/citologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodosRESUMO
Olfactory ensheathing cells (OECs) are a unique glial population found in both the peripheral and central nervous system: they ensheath bundles of unmyelinated olfactory axons from their peripheral origin in the olfactory epithelium to their central synaptic targets in the glomerular layer of the olfactory bulb. Like all other peripheral glia (Schwann cells, satellite glia, enteric glia), OECs are derived from the embryonic neural crest. However, in contrast to Schwann cells, whose development has been extensively characterised, relatively little is known about their normal development in vivo. In the Schwann cell lineage, the transition from multipotent Schwann cell precursor to immature Schwann cell is promoted by canonical Notch signalling. Here, in situ hybridisation and immunohistochemistry data from chicken, mouse and human embryos are presented that suggest a canonical Notch-mediated transition also occurs during OEC development.
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Neuroglia/citologia , Receptor Notch1/metabolismo , Animais , Diferenciação Celular , Embrião de Galinha , Galinhas , Embrião de Mamíferos , Humanos , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Bulbo Olfatório/embriologiaRESUMO
Production of olfactory bulb neurons occurs continuously in the rodent brain. Little is known, however, about cellular diversity in the glutamatergic neuron subpopulation. In the central nervous system, the basic helix-loop-helix transcription factor NeuroD1 (ND1) is commonly associated with glutamatergic neuron development. In this study, we utilized ND1 to identify the different subpopulations of olfactory bulb glutamategic neurons and their progenitors, both in the embryo and postnatally. Using knock-in mice, transgenic mice and retroviral transgene delivery, we demonstrate the existence of several different populations of glutamatergic olfactory bulb neurons, the progenitors of which are ND1+ and ND1- lineage-restricted, and are temporally and regionally separated. We show that the first olfactory bulb glutamatergic neurons produced - the mitral cells - can be divided into molecularly diverse subpopulations. Our findings illustrate the complexity of neuronal diversity in the olfactory bulb and that seemingly homogenous neuronal populations can consist of multiple subpopulations with unique molecular signatures of transcription factors and expressing neuronal subtype-specific markers.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Ácido Glutâmico/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Bulbo Olfatório/citologia , Bulbo Olfatório/crescimento & desenvolvimento , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular , Linhagem da Célula , Expressão Ectópica do Gene , Ventrículos Laterais/citologia , Ventrículos Laterais/crescimento & desenvolvimento , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Proteínas com Domínio T/metabolismoRESUMO
Progress in Parkinson's disease (PD) research has been hampered by the lack of an appropriate model which exhibits the core pathology seen in the human brain. Recent advances in deriving cells with neuronal phenotypes from patients with neurodegenerative disorders through cellular reprogramming offer a unique tool for disease modelling and may help shed light on the molecular pathogenesis that drives the progression of the disease. This technology may also help in establishing platforms for drug screening and open up exciting new prospects for cell grafting. In this review, we will discuss progress made in differentiating stem cells into authentic dopamine neurons and where we stand with respect to clinical trials with these cells in patients with PD. We will also examine the various approaches used in cellular reprogramming and their differentiation into patient-specific midbrain dopamine neurons, with an emphasis particularly on modelling familial cases of PD to recapitulate disease phenotypes. This review will highlight some of the challenges that need to be addressed for this technology to have any potential clinical application in cell therapy and personalised medicine.