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1.
Neurobiol Dis ; 170: 105753, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35569719

RESUMO

Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization of neuronal mitochondria is significantly increased in astrocytes isolated from AD mouse brains. We also demonstrate that the degradation of neuronal mitochondria by astrocytes is increased in AD mice at the age of 6 months onwards. Furthermore, we demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and AD astrocytes together with significant increases in the mitophagy regulator and reactive oxygen species in aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/metabolismo , Camundongos , Mitofagia , Neurônios/metabolismo
2.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575854

RESUMO

Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are novel evolutionary conserved trophic factors, which exhibit cytoprotective activity via negative regulation of unfolded protein response (UPR) and inflammation. Despite multiple reports demonstrating detrimental effect of MANF/CDNF downregulation, little is known about the control of their expression. miRNAs-small non-coding RNAs-are important regulators of gene expression. Their dysregulation was demonstrated in multiple pathological processes and their ability to modulate levels of other neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was previously reported. Here, for the first time we demonstrated direct regulation of MANF and CDNF by miRNAs. Using bioinformatic tools, reporter assay and analysis of endogenous MANF and CDNF, we identified that miR-144 controls MANF expression, and miR-134 and miR-141 downregulate CDNF levels. We also demonstrated that this effect is human-specific and is executed via predicted binding sites of corresponding miRNAs. Finally, we found that miR-382 suppressed hCDNF expression indirectly. In conclusion, we demonstrate for the first time direct regulation of MANF and CDNF expression by specific miRNAs, despite the fact their binding sites are not strongly evolutionary conserved. Furthermore, we demonstrate a functional effect of miR-144 mediated regulation of MANF on ER stress response markers. These findings emphasize that (1) prediction of miRNA targets based on evolutionary conservation may miss biologically meaningful regulatory pairs; and (2) interpretation of miRNA regulatory effects in animal models should be cautiously validated.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , Fatores de Crescimento Neural/genética , Interferência de RNA , Regiões 3' não Traduzidas , Linhagem Celular , Estresse do Retículo Endoplasmático , Humanos , RNA Mensageiro/genética
3.
Mov Disord ; 35(12): 2279-2289, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32964492

RESUMO

BACKGROUND: Parkinson's disease (PD) is associated with proteostasis disturbances and accumulation of misfolded α-synuclein (α-syn), a cytosolic protein present in high concentrations at pre-synaptic neuronal terminals. It is a primary constituent of intracellular protein aggregates known as Lewy neurites or Lewy bodies. Progression of Lewy pathology caused by the prion-like self-templating properties of misfolded α-syn is a characteristic feature in the brains of PD patients. Glial cell line-derived neurotrophic factor (GDNF) promotes survival of mature dopamine (DA) neurons in vitro and in vivo. However, the data on its effect on Lewy pathology is controversial. OBJECTIVES: We studied the effects of GDNF on misfolded α-syn accumulation in DA neurons. METHODS: Lewy pathology progression was modeled by the application of α-syn preformed fibrils in cultured DA neurons and in the adult mice. RESULTS: We discovered that GDNF prevented accumulation of misfolded α-syn in DA neurons in culture and in vivo. These effects were abolished by deletion of receptor tyrosine kinase rearranged during transfection (RET) or by inhibitors of corresponding signaling pathway. Expression of constitutively active RET protected DA neurons from fibril-induced α-syn accumulation. CONCLUSIONS: For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded α-syn propagation in DA neurons, uncovered underlying receptors, and investigated the involved signaling pathways. These results demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD. © 2020 International Parkinson and Movement Disorder Society.


Assuntos
Neurônios Dopaminérgicos , Corpos de Lewy , Animais , Neurônios Dopaminérgicos/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Humanos , Corpos de Lewy/metabolismo , Mesencéfalo/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-ret , Transdução de Sinais , alfa-Sinucleína/metabolismo
4.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801298

RESUMO

MicroRNAs are post-transcriptional regulators of gene expression, crucial for neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases neuronal vulnerability to cellular stress and may contribute to the development and progression of neurodegenerative diseases. All major neurodegenerative disorders are also associated with oxidative stress, which is widely recognized as a potential target for protective therapies. Albeit often considered separately, microRNA networks and oxidative stress are inextricably entwined in neurodegenerative processes. Oxidative stress affects expression levels of multiple microRNAs and, conversely, microRNAs regulate many genes involved in an oxidative stress response. Both oxidative stress and microRNA regulatory networks also influence other processes linked to neurodegeneration, such as mitochondrial dysfunction, deregulation of proteostasis, and increased neuroinflammation, which ultimately lead to neuronal death. Modulating the levels of a relatively small number of microRNAs may therefore alleviate pathological oxidative damage and have neuroprotective activity. Here, we review the role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) disease, and amyotrophic lateral sclerosis (ALS). We also discuss the problems associated with the use of oversimplified cellular models and highlight perspectives of studying microRNA regulation and oxidative stress in human stem cell-derived neurons.


Assuntos
Doença de Alzheimer/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Doença de Huntington/metabolismo , MicroRNAs/genética , Estresse Oxidativo/genética , Doença de Parkinson/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Regulação da Expressão Gênica , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , MicroRNAs/classificação , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oxirredução , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transdução de Sinais
5.
Curr Protoc Neurosci ; 91(1): e88, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32049438

RESUMO

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non-motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α-synuclein, LRRK2, DJ-1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α-synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD-like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector-mediated transgene expression and, recently, injections of misfolded α-synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre-clinical PD research towards successful disease-modifying therapy. © 2020 The Authors.


Assuntos
Neurotoxinas/toxicidade , Transtornos Parkinsonianos , Animais , Corpo Estriado/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/ultraestrutura , Avaliação Pré-Clínica de Medicamentos/métodos , Previsões , Estudo de Associação Genômica Ampla , Técnicas Histológicas , Humanos , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/genética , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Praguicidas/toxicidade , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Ratos , Substância Negra/efeitos dos fármacos , Sinucleinopatias/genética , Sinucleinopatias/patologia , alfa-Sinucleína/biossíntese , alfa-Sinucleína/genética
6.
Cell Death Dis ; 8(5): e2813, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28542144

RESUMO

MicroRNAs (miRs) are important post-transcriptional regulators of gene expression implicated in neuronal development, differentiation, aging and neurodegenerative diseases, including Parkinson's disease (PD). Several miRs have been linked to PD-associated genes, apoptosis and stress response pathways, suggesting that deregulation of miRs may contribute to the development of the neurodegenerative phenotype. Here, we investigate the cell-autonomous role of miR processing RNAse Dicer in the functional maintenance of adult dopamine (DA) neurons. We demonstrate a reduction of Dicer in the ventral midbrain and altered miR expression profiles in laser-microdissected DA neurons of aged mice. Using a mouse line expressing tamoxifen-inducible CreERT2 recombinase under control of the DA transporter promoter, we show that a tissue-specific conditional ablation of Dicer in DA neurons of adult mice led to decreased levels of striatal DA and its metabolites without a reduction in neuronal body numbers in hemizygous mice (DicerHET) and to progressive loss of DA neurons with severe locomotor deficits in nullizygous mice (DicerCKO). Moreover, we show that pharmacological stimulation of miR biosynthesis promoted survival of cultured DA neurons and reduced their vulnerability to thapsigargin-induced endoplasmic reticulum stress. Our data demonstrate that Dicer is crucial for maintenance of adult DA neurons, whereas a stimulation of miR production can promote neuronal survival, which may have direct implications for PD treatment.


Assuntos
Envelhecimento/metabolismo , Neurônios Dopaminérgicos/metabolismo , MicroRNAs/metabolismo , Neuroproteção , Ribonuclease III/metabolismo , Alelos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Neurônios Dopaminérgicos/patologia , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Deleção de Genes , Mesencéfalo/metabolismo , Camundongos Knockout , MicroRNAs/genética , Atividade Motora/efeitos dos fármacos , Degeneração Neural/genética , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neuroproteção/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tapsigargina/farmacologia
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