Endogenous Mechanisms of Neuroprotection: To Boost or Not to Be

Marmolejo-Martínez-Artesero, Sara; Casas, Caty

doi:10.3390/cells10020370

Cited by 16 publications

(13 citation statements)

References 214 publications

(290 reference statements)

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“…Thus, our main goal is to establish the mechanisms by which GRP78 overexpression leads to neuroprotection using non-transgenic models of neurodegeneration. In particular, exploiting the anatomical and technical advantages of several models of spinal motoneuron (MN) axotomy, we previously reported that nerve root avulsion (RA) initiates a retrograde process of motor neurodegeneration (80% of MN loss over a month post-injury) characterized by the presence of ER stress, autophagy flux blockage, vesicle, and protein trafficking arrest, the concurrence of apoptosis/antiapoptosis/anoikis initiation but the absence of an effective apoptosis execution [20,25,28]. We discovered that the expression of GRP78 is lost around 5 days after RA within damaged MNs and that its forced overexpression allows their survival after axotomy.…”

Section: Introductionmentioning

confidence: 99%

GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy

et al. 2021

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An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.

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Section: Introductionmentioning

confidence: 99%

GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy

et al. 2021

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“…Аутофагия играет существенную роль в снижении производства активных форм кислорода (АФК) и способствует митохондриальному обновлению и биогенезу, что увеличивает продолжительность жизни за счет более позднего начала возрастных осложнений. Нерегулируемая аутофагия может привести к клеточной дисфункции, аномальному накоплению белка, протеотоксичности и, как следствие, развитию нейродегенеративных заболеваний [66]. Ограничение калорийности питания является мощным индуктором процесса аутофагии и это единственное немедикаментозное вмешательство, способствующее увеличению продолжительности жизни у пациентов [67][68][69].…”

Section: обзорunclassified

Effect of caloric restriction on aging and neurodegenerative diseases

Фефелова¹,

Мурашев²

2022

Zhurnal «Patologicheskaia Fiziologiia I Eksperimental`naia Terapiia»

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Исследования на моделях млекопитающих демонстрируют, что ограничение калорийности питания замедляет процессы старения, увеличивает продолжительность жизни и отодвигает начало ряда возрастных заболеваний, в том числе нейродегенеративных. При ограничении калорийности питания организм переходит в режим поддержания жизнеспособности, что реализуется за счет включения программ стрессоустойчивости и замедления процессов роста и репродукции. К реализации данных программ приводят выраженные изменения внутриклеточных процессов: активация репарации макромолекул и восстановление длины теломер хромосом, что способствует поддержанию стабильности генома и протеома, выживаемости стволовых клеток. Кроме того, происходит перепрограммирование метаболических процессов и изменение их скорости, в том числе через влияние рестрикции питания на эпигенетические механизмы контроля. Ограничение калорий - это диетическая стратегия, которая может оказать влияние на скорость развития нейродегенерации. Таким образом, диета и питание являются одними из наиболее значимых модифицируемых внешних факторов, регулирующих метаболизм клеток, что определяет перспективные траектории изучения их влияния на механизмы развития нейровоспалительных и нейродегенеративных процессов. В обзоре обсуждаются механизмы, посредством которых клетки переходят на иные программы жизнеобеспечения при рестрикции питания, что проявляется изменениями процессов нейровоспаления, нейрогенеза в ответ на реализацию эпигенетических программ, запуска ответа сиртуинов, изменений в митохондриальном биогенезе. Research using mammalian models has shown that calorie restriction slows the aging process, increases life expectancy, and delays the onset of a number of age-related diseases, including neurodegenerative diseases. During caloric restriction, the organism goes into a viability maintenance mode, which is realized by the activation of stress resistance programs and the slowing of growth and reproduction processes. Very pronounced changes in intracellular processes lead to the realization of these programs, which include activation of mechanisms for repair of macromolecules and for restoration of the length of chromosome telomeres. This contributes to maintaining the stability of the genome and proteome, and the survival of stem cells. In addition, metabolic processes are reprogrammed, and their rate changes due to the influence of nutritional restriction on epigenetic control mechanisms. Caloric restriction is a dietary strategy that may have an impact on the rate of neurodegeneration. Therefore, diet and nutrition are among the most significant modifiable external factors that regulate cell metabolism. This approach offers promising ways for studying the influence of diet and nutrition on the mechanisms of neuroinflammatory and neurodegenerative processes. This article discusses mechanisms that change cellular function such that cells switch to life support programs during nutritional restriction. This is manifested by changes in the processes of neuroinflammation and neurogenesis in response to epigenetic programs that trigger the sirtuin response and change mitochondrial biogenesis.

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“…One promising cerebroprotective strategy for stroke is to leverage cellular self-healing mechanisms that have been refined over time by nature (Yang and Paschen, 2017;Marmolejo-Martinez-Artesero et al, 2021). Among these mechanisms is activation of the unfolded protein response (UPR; Yang and Paschen, 2016;Li and Yang, 2021).…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke

Li²,

Lu³

et al. 2022

Front. Cell. Neurosci.

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Objective: Brain ischemia leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen and consequently, ER stress. To help cells restore ER function, a series of adaptive stress response pathways, collectively termed the unfolded protein response (UPR), are activated. We have previously demonstrated that the UPR pathway initiated by ATF6 is pro-survival in transient ischemic stroke. However, the effect of ATF6 activation on the outcome after permanent ischemic stroke remains unknown. Here, we addressed this knowledge gap.Method: sATF6-KI mice with functional short-form ATF6 (sATF6) predominantly expressed in forebrain neurons were subjected to two ischemic stroke models: photothrombotic stroke and permanent middle cerebral artery occlusion (pMCAO). Both short-term and long-term functional outcomes were evaluated. Changes in neuroinflammation and cerebrovascular density after pMCAO were also assessed.Results: Compared to littermate controls, sATF6-KI mice performed significantly better in open field, cylinder, and foot fault tests on day 1 or 3 after photothrombotic stroke. However, on days 7 and 14 after stroke, the performance of these functional tests was not significantly different between groups, which is likely related to mild brain damage associated with this stroke model. Thus, to evaluate the long-term effects of ATF6 activation in permanent stroke, we turned to our pMCAO model. We first found that on day 4 after pMCAO, functional outcome was better, and infarct volumes were smaller in sATF6-KI mice vs controls. Next, the 15-day stroke outcome study indicated that compared to control mice, sATF6-KI mice consistently exhibited improved performance in neurologic scoring, tight rope test, and tape removal test, after pMCAO. Moreover, sATF6-KI mice showed higher vascular density and lower activation of both astrocytes and microglia around stroke regions on day 16 after pMCAO.Conclusions: Here, we presented the first evidence that activation of the ATF6 UPR branch is protective in permanent ischemic stroke, which further supports the therapeutic potential of targeting the ATF6 pathway in stroke.

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Endogenous Mechanisms of Neuroprotection: To Boost or Not to Be

Cited by 16 publications

References 214 publications

GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy

GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy

Effect of caloric restriction on aging and neurodegenerative diseases

Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke

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