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Regulation of neurogenesis by calpains: revelance for post-injury brain repair
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Abstract(s)
No cérebro adulto dos mamíferos, novos neurónios são continuamente adicionados em duas regiões neurogénicas principais: a zona subventricular, nas paredes dos ventrículos laterais, e a zona subgranular, no giro dentado do hipocampo. As células estaminais neurais presentes nestes nichos têm a capacidade de proliferar e dar origem a neuroblastos em migração, que acabam por se diferenciar em novos neurónios. Curiosamente, no evento de uma lesão cerebral, a proliferação das células estaminais neurais aumenta, possivelmente numa tentativa de reparação do dano cerebral. No entanto, esta reparação é limitada pela redução da migração celular ou pela diminuição da sobrevivência dos novos neurónios. Descobrir como aumentar a eficiência da neurogénese após lesão poderá ser portanto benéfico para a reparação cerebral. Por outro lado, o dano cerebral também pode activar diversas protéases, incluindo as calpaínas. As calpaínas são proteases ubíquas, sabendo-se que estão envolvidas na proliferação, migração e diferenciação celular em diversos sistemas. No cérebro, a inibição das calpaínas tem efeito neuroprotector, mas os seus efeitos na neurogénese permanecem ainda pouco conhecidos. A delecção do inibidor endógeno das calpaínas, a calpastatina, já anteriormente mostrou ser capaz de reduzir as primeiras fases da neurogénese in vivo. No presente trabalho, mostramos que a inibição das calpaínas é capaz de reverter este efeito, implicando-as ainda mais no processo. Uma vez que a inibição das calpaínas parece ser um alvo promissor para o aumento da neurogénese após lesão, avaliámos várias fases do processo neurogénico, bem como a recuperação das alterações do comportamento cognitivo após lesão no hipocampo induzida por crises epilépticas, em murganhos com sobrexpressão de calpastatina. Avaliámos ainda os efeitos da delecção das calpaínas 1 e 2 nas primeiras fases da neurogénese no hipocampo. Observámos que o padrão de aumento da neurogénese após lesão foi mantido em murganhos com sobrexpressão de calpastatina, apesar de alguma recuperação cognitiva indicar algum grau de neuroprotecção, que por si só poderá ter mascarado a influência da inibição das calpaínas na neurogénese. Murganhos com falta de calpaínas, no entanto, não apresentaram alterações das primeiras fases da neurogénese no hipocampo, sugerindo que as calpaínas apenas afectam este processo quando a sua actividade está acima de um certo limite, abaixo do qual a neurogénese não é afectada. Isto significa que a inibição das calpaínas poderá potencialmente ser útil para prevenir a redução da formação de novos neurónios após lesão, caso os níveis de actividade das calpaínas possam ser reduzidos abaixo de um certo limite.
New neurons are continuously added in the adult mammalian brain, in two main neurogenic regions: the subventricular zone, in the walls of the lateral ventricles, and the subgranular zone, in the dentate gyrus of the hippocampus. Neural stem cells present in these niches are able to proliferate and originate migrating neuroblasts, which ultimately differentiate into new neurons. Interestingly, in the event of a brain lesion, neural stem cell proliferation increases, possibly in an attempt to repair the damage. However, this repair is limited by impaired cell migration or decreased survival of new neurons. Discovering how to increase the efficiency of post-injury neurogenesis may therefore be beneficial for brain repair. On the other hand, brain damage can also activate several proteases, including calpains. Calpains are ubiquitous proteases known to be involved in cell proliferation, migration and differentiation in several systems. In the brain, calpain inhibition has been shown to be neuroprotective, but their effects on neurogenesis remain elusive. Deletion of the endogenous inhibitor of calpains, calpastatin, has previously been shown to impair early stages of neurogenesis in vivo. In the present work, we show that calpain inhibition is able to reverse this impairment, further implicating them in the process. Since calpain inhibition offers a promising target for the enhancement of post-injury neurogenesis, we evaluated different stages of the process and cognitive behavior recovery after seizure-induced hippocampal lesion in mice overexpressing calpastatin, and also the effects of the absence of conventional calpains on the early stages of hippocampal neurogenesis. We observed that the pattern of enhancement of post-injury neurogenesis was mostly maintained in mice overexpressing calpastatin, though some cognitive recovery indicates some degree of neuroprotection, which by itself may have masked the influence of calpain inhibition on neurogenesis. Mice lacking calpains, however, presented unaltered levels of the early stages of hippocampal neurogenesis, suggesting that calpains only affect this process when their activity is over a certain threshold, under which neurogenesis is not affected. This means that calpain inhibition could potentially be useful to stimulate the formation of new neurons after injury, given that the levels of calpain activity could be reduced under a certain threshold.
New neurons are continuously added in the adult mammalian brain, in two main neurogenic regions: the subventricular zone, in the walls of the lateral ventricles, and the subgranular zone, in the dentate gyrus of the hippocampus. Neural stem cells present in these niches are able to proliferate and originate migrating neuroblasts, which ultimately differentiate into new neurons. Interestingly, in the event of a brain lesion, neural stem cell proliferation increases, possibly in an attempt to repair the damage. However, this repair is limited by impaired cell migration or decreased survival of new neurons. Discovering how to increase the efficiency of post-injury neurogenesis may therefore be beneficial for brain repair. On the other hand, brain damage can also activate several proteases, including calpains. Calpains are ubiquitous proteases known to be involved in cell proliferation, migration and differentiation in several systems. In the brain, calpain inhibition has been shown to be neuroprotective, but their effects on neurogenesis remain elusive. Deletion of the endogenous inhibitor of calpains, calpastatin, has previously been shown to impair early stages of neurogenesis in vivo. In the present work, we show that calpain inhibition is able to reverse this impairment, further implicating them in the process. Since calpain inhibition offers a promising target for the enhancement of post-injury neurogenesis, we evaluated different stages of the process and cognitive behavior recovery after seizure-induced hippocampal lesion in mice overexpressing calpastatin, and also the effects of the absence of conventional calpains on the early stages of hippocampal neurogenesis. We observed that the pattern of enhancement of post-injury neurogenesis was mostly maintained in mice overexpressing calpastatin, though some cognitive recovery indicates some degree of neuroprotection, which by itself may have masked the influence of calpain inhibition on neurogenesis. Mice lacking calpains, however, presented unaltered levels of the early stages of hippocampal neurogenesis, suggesting that calpains only affect this process when their activity is over a certain threshold, under which neurogenesis is not affected. This means that calpain inhibition could potentially be useful to stimulate the formation of new neurons after injury, given that the levels of calpain activity could be reduced under a certain threshold.
Description
Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016
Keywords
Neurogénese Lesão cerebral Calpaínas Hipocampo Memória Adult neurogenesis Brain injury Calpains Hippocampus Memory