Molecular Biology and Nanomedicine

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Review: Role of Autophagy in Nervous System Injury





Review

Review: Role of Autophagy in Nervous System Injury

ZeYong Xie 1, Erdong Shen 2,*

1 Department of Internal Medicine, Linxiang Zhongya Hospital, Yueyang414300, China; biya34443809@163.com

2 Department of Oncology (The 3rd Ward), The First People’s Hospital of Yueyang, Yueyang 414000, China

* Correspondence to:sss_erdong@163.com (Shen E)

Received: 21 May 2020; Accepted: 12 June 2020; Published:18 June 2020

Abstract: Autophagy is characterized by a series of cell activities in which cytoplasmic components including organelles and proteins are transferred to the lysosomal compartment for further degradation, and has been confirmed as a pivotal regulator in the maintenance of cellular homeostasis. Currently, autophagy has been extensively involved in the study and treatment of nerve injury and it exhibits a dual role in nerve injury. Besides, it also facilitates the birth of valuable therapeutic tactics in treating lung pathologies. Since 2005, its functions in cardioprotection also catch many researchers’ attention. Yet most noticeable is the fact that autophagy is gaining an increasing status in the study of the repair of nerve injury with high clinical value as presented in this study.

Keywords: autophagy; nervous system injury;repair

1. Introduction

Cells of the nervous system greatly differ as per their molecular characteristics, physiological activity, and morphology. Neurons are highly specialized cells that are able to receive and transmit electrical signalling along and across their body [1]. Cells of an organism face with various types of insults during their lifetime, like exposure to toxins, metabolic problems, ischemia/reperfusion, physical trauma, genetic diseases, neurodegenerative diseases. In this context, autophagy is one of the mechanisms that supports cell survival.

First proposed by Christian de Duve in 1963, autophagy (also known as macroautophagy) refers to a lysosome-mediated degradation process in which non-basic or damaged cellular elements are recycled and by which cells are able to obtain intracellular lipids, organelles and proteins and transfer them to lysosomal compartment [2,3]. It is most typically characterized by the formation of endomembrane organelles or the so-called autophagosomes [4]. Although diverse sources may be included in the development of autophagosome membranes, the question of whether and where those membrane sources will fuse in autophagosome biogenese still remains unsolved [5]. Either being non-selective or selective, it is primarily classified into three types, namely macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), and the first type remains to be the most widely and popularly investigated up till now [6]. Moreover, autophagy-related proteins, once being post-translationally regulated in a complicated way, adds extra entry points for disturbance to other kinds of cellular processes and contributes to the definition of cell-type-specific regulations of autophagy [7].

As a neurodegenerative disease, autophagy is capable of protecting organelle function, cleaning up the toxic cellular waste products and offering substrates which ensures metabolism during starvation [8]. Basically speaking, its functions are of undeniable significance in promoting physical development and growth as it can supply energy for cellular activities, maintain a stable intracellular environment and remove aged, useless or malfunctioned cells. Despite the undeterminable criteria in the confirmation of autophagy, current approaches for its monitoring include transmission electron microscopy (TEM), Atg8/LC3 detection and quantification, p62 and related LC3 binding protein turnover assays, and detection of some autophagy-related markers such as Atg9, ATG14, DRAM etc. [9].

To date, study of autophagy has been widely stretched into a variety of pathophysiological diseases such as metabolic problem, cardiovascular and pulmonary diseases, neurodegenerative disorders, cancers, and also in physiological responses to exercise and aging [10]. In the central nervous system, an increase in autophagy can be regarded as either physiologic or supraphysiologic and it is dependent on the pressure of intracellular substrate specifically aiming at autophagy and on the capacity of the cellular autophagic machinery [11]. Particularly worth mentioning is the fact that during the autophagy, neurons are considered to be more vulnerable to disruptions or interferences and autophagy-related genes, if mutate, can give rise to diverse neurodegenerative illnesses including Alzheimer’s disease, Parkinson’s disease etc. [12]. For example, White once explored the role played by autophagy in cancer, claiming that it is a tissue-specific regulator of hemeostasis and survival, a tumor suppressor, and also a tumor promotor [8]. Nian Xiong et al. conducted a deep and comprehensive analysis of the function of autophagy in protecting against Parkinson’s disease (PD) for its promoters can prevent rotenone-induced toxicity yet its inhibitors in SH-SY5Y can achieve an opposite effect [13].

Although there have been abundant researches focusing on the treatment of major neurologic disorders, only a small portion of them have achieved substantial progress in improving neurologic symptoms by adopting traditional symptomatic therapies for neurorepair [14]. This review primarily offers an overview of the role of autophagy in nervous system injury, with a focus specifically placed on the mechanisms and their considerable impact on certain neurological diseases.

2. Genesis and Categorization of Autophagy

Autophagy is defined as a homeostatic process which, under most circumstances, happens in all eukaryotic cells and relates to the separation of cytoplasmic constituents in double-membraned autophagosomes [10]. Generally, autophagy develops in the following steps. First, phagophore, a double-membrane structure, comes into being around the cytosolic substances when cells are under starvation of other kinds of stressful circumstances. Second, autophagosome is then formed when modulated by the Atg1-Atg13-Atg17-Atg31-Atg29 kinase complex. Third, when the autophagosome is in appropriate conditions, it traffics to and fuses with an endosome and/or lysosome, thus forming an autolysosome. Fourth, the membrane of autolysosome is lysed and intracellular components are further degraded so as to provide cells with basic nutrients and energy [15].

Admittedly, altogether 3 types of autophagy have been ubiquitously included in the study of this field: microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA). With the least research interest, microautophagy is characterized by a direct devour of cytosolic substances at a boundary membrane by autophagic channels mediating invagination and vesicle scission into the lumen and shares no dependent connection with canonical autophagy-like degradation. Macroautophagy remains to be the most popular type among researchers and it involves a double-membrane structure responsible for the clearance of cytosolic components and the formation of autophagosomes. With regard to CMA, it refers to the process greatly dependent on the cytosolic chaperone protein HSPA8/HSC70 able to selectively distinguish some client proteins with specific motifs which are subsequently transferred to the lysosome membrane[6,16,17].

3. Molecular Regulatory Mechanism of Autophagy

Under the regulation of many autophagy-related genes (Atg), it has been widely recognized as a highly conservative intracellular mechanism. Those Atgs and their related proteins can exert diverse and differentiated impact on the occurrence and development of autophagy in various stages, among which the formation of autophagosome deserves our greatest attention. There are two pivotal signaling complexes indispensable for the appearance of autophagosome: ULK, which directly sensors nutrients and energy for autophagy activation, and Beclin1-PI3KC3, which produces PI3P contributable to the collection of autophagy effectors [18].

To be more specific, two pathways, namely the mechanistic target of rapamycin (mTOR) signaling pathway and the Beclin1 signaling pathway, are core members in the molecular mechanism of autophagy. mTOR, a serine/threonine kinase, serves as a crucial participator in regulating cell survival and metabolism and one of its derivatives, mTORC1, can affect protein synthesis, growth, and autophagy by combining nutrient signals and growth factors [19]. mTOR downregulates and prevents ULK1 from binding with Atg13 and FIP200 which are essential for the formation of autophagosome and it is inhibited by activated adenosine monophosphate protein-activated kinase (AMPK) upon the induction of autophagy[20,21]. Beclin1 pathway is primarily controlled by Atg6 and Beclin-1. Beclin-1, also called Atg6, belongs to the autophagy-related family of proteins and is frequently found in eukaryotes [22]. Regulating the position of some autophagy proteins into the precursor of autophagic bodies, Beclin-1 has been proved to play a vital role in the shaping of mammalian autophagy [23]. Specifically, it acts as a regulator in the process of PtdIns3KC3-dependent generation of phosphatidylinositol 3-phosphate (PtdIns(3)P) as well as the following collection of additional Atg proteins [22]. Noticeably, during the formation and extension of autophagosome, the conjugations of Atg12 to Atg5 and of LC3-I to the membrane lipid phosphatidylethanolamine are also of great significance [20].

4. Autophagy in Parkinson’s Disease

Affecting almost 1–2% of people aged over 60 years worldwide, Parkinson’s Disease (PD) has been regarded as the second most popular neurodegenerative disorder despite an uncertain pathogenesis [13]. It is featured by a sharp decrease of the midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc) together with Lewy bodies (LBs), a ubiquitylated α-synuclein-containing intracytoplasmic inclusions, in the alive SNpc neurons [24]. According to the biochemical and imaging data, it is implied that approximately an over 70% decline in dopamine neurons occur upon the diagnosis of PD and this trend will continue as the PD progresses [25]. In light of the fact that the lack of Atg genes can give rise to neurodegeneration and irregular accumulation of proteins, similar to the pathologic characteristics of PD, it is natural to observe the involvement of conditionally impaired autophagy in the study of PD [26].

In the past, evidence indicating the relations between the PD pathology and macroautophagy has been increasing. For example, it has been observed that α-synuclein is partly removed through autophagy process and the mutated or malfunctioned PARK2, responsible for the encoding of the ubiquitin ligase protein Parkin, usually account for the early occurrence of PD, and can play a regulatory role in the disposal of abnormal mitochondria through autophagy [27,28]. Plowey et al. found out that mutated leucine-rich repeat kinase 2 (LRRK2) gene, as the most commonly found monogenetic cause of PD, is able to promote abnormality in neurites by depending on autophagy [29]. During the exploration of PD on the genetic basis, Beilina and Cookson further checked how genes for PD are connected with autophagy-lysosomal system and presumed that a number of recognized PD genes exert their functions in certain signaling pathways which affect either the turnover of mitochondria through mitophagy, or the turnover of some vesicular structures through macroautophagy or CMS, or the general function of lysosome [30]. Besides, by means of ex vivo and in vitro models of PD, Arduíno et al. confirmed that mitochondria can directly influence the autophagic ability which follows incomplete microtubule trafficking driven by multifunctional mitochondria. Hence, they demonstrated that mitochondria and mitochondria-dependent intracellular traffic have decisive impact on the autophagy in PD[24].

Another type of autophagy, CMA, has also been acknowledged as an initiator of PD since its two important regulators, lysosomal-associated membrane protein (lamp) 2A and heat shock cognate (hsc) 70 protein, both appear in brains of PD patients [31]. Also in another previous study, there was evidence showing that CMA can have a big influence on the pathogenesis of PD in that up-regulated CMA activities result in a degradation of overloaded α-synuclein, the aggregation of which serves as a promoter in the death of dopaminergic neurons [32]. Alvarez et al. observed that the CMA activities were decreased in brains of PD patients, supporting the significance of autophagy in the pathogenesis of PD, and implicated the possible therapeutic role of α-synuclein-related pathways in treating PD [33].

For patients with PD, because the grouping of misfolded proteins and the emergence of protein aggregates can lay negative impact on cell function and death, their disposal or clearance appears to be extremely crucial in attenuating the progression of PD [25]. Previously, it has been proved that since overexpressed transcription factor EB (TFEB) is conducive to the amelioration in lysosomal functions which can further ensure strong neuroprotection by removing α-synuclein oligomers, TFEB has also been identified as a hopeful therapeutic target in PD due to its targeting at neuroprotection and disease improvement [34]. Specifically, some researchers found out that Piperine (PIP), a Chinese medicine mainly for treating inflammation and toxicity, can act as an useful agent in treating PD patients due to its neuroprotective functions by inducing autophagy [35].

To sum up, considering that effective therapeutic strategies of PD are in scarcity at present, studies of autophagy pathway in this field have drawn wide-ranged attention and have been shown as of great significance and a promising future in helping more patients who suffer from PD.

5. Autophagy in Cerebral Ischemia

As the most vulnerable organ to diseases like ischemia, brain harbors numerous neurons that are especially responsive to such injuries and exhibited different degrees of vulnerability among various neuronal groups [14]. Over the years, whether enhanced autophagic activities can positively regulate neuronal death in autophagy remains controversial and unsure [36].

Cerebral ischemia (CI) refers to a diminution of cerebral blood flow below the key thresholds, primarily induced by unilateral common carotid artery occlusion and hypoxia [36,37]. It usually results in damage to brain energy metabolism by releasing glutamate into the extracellular area at an excessive amount [14]. According to its severity, it is classified into the global ischemia in which damage happens in the whole brain, and the focal ischemia in which injury can only be observed in some regions with a low perfusion [37]. When it progresses into a severe state, the neuroprotective mechanisms of G-CSF is hence started as exemplified by inhibited glutamate release, weakened inflammation, antiapoptotic activities as well as downregulated edema formation [14].

Recently, some reports aiming at the role of autophagy in CI patients implicated that by acting as a stress response, autophagy is likely to take part in the pathophysiology of CI [38]. In spite of the fact that autophagy can give rise to ischemia, how it participates in the reperfusion phase after ischemia and lays impact on the life of neurons is still left to be further investigated. Recent evidence proved that autophagy can provide protection during reperfusion phase after ischemia, thus contributing to mitophagy-associated mitochondrial disposal as well as suppression of downstream apoptosis [39]. Shi et al. also demonstrated that excessive autophagy acts as a positive player in causing neuron death in brains suffering from CI [36]. To be more specific, some researchers endeavored to further figure out how autophagy is involved in CI. For example, in a previous study, it has been reported that nicotinamide phosphoribosyl-transferase (Nampt), a rate-limiting enzyme found in mammalian NAD (+) biosynthesis, can upregulate the survival of neurons by eliciting autophagy through the modulation of TSC2-mTOR-S6K1 signaling pathway dependent on SIRT1 during the development of CI [38].

When it comes to the treatment for CI, ischemic post-conditioning (IPOC), or treating in a stuttered way, has exhibited surprising and original functions in the therapy of ischemia as it can greatly attenuate programmed cell apoptosis, alleviate ischemic injuries, and guarantee a better neurological outcome. Gao et al. established focal CI models combined with middle cerebral artery (MCA) occlusion and transient common carotid artery (CCA) occlusion and demonstrated that inhibited autophagic pathway enables IPOC-induced neuroprotection to better defend against focal CI, which is also of great importance in treating CI [40]. miRNA-210, as a hypoxia-induced miRNA, is considered to be important in modulating a series of biological processes such as angiogenesis in response to ischemic injury in brains. Relevant data showed that increased expression of miR-210 is capable of activating the Notch signaling pathway, thus enabling the occurrence of angiogenesis after CI [41]. Balduini et al. mentioned in their study that autophagy may become a crucial member of the integrated pro-survival signaling pathway together with the PI3K-Akt- mTOR axis and once activated, it can exert great impact on the preconditioning of pharmacological and ischemic diseases [42].

In conclusion, studies of autophagy in CI are in a strong supply. It has been admittedly accepted that autophagy is activated both in CI and in reperfusion after CI. Nevertheless, due to the underlying limitations in the study of autophagy or a lack of multiple research approaches in the detection of autophagy, how it functions in the subsequent progression of CI and CI-related diseases still needs to be further investigated. Noticeably, differences among all kinds of animal models and experiments in vitro and in vivo may place negative influence on the credibility or accuracy of research results. Therefore, a deeper and more comprehensive study of the relationship between autophagy and CI and its potential mechanism is able to offer greater insights into the pursuit of innovative and promising therapeutic targets.

6. Autophagy in Intracerebral Hemorrhage

Among all types of stroke, intracerebral hemorrhage (ICH), with high mortality and mobility rates, is counted as the least treatable neurological disorder and approximately millions of people are under its attack worldwide [43]. In brains, when primary and secondary injury caused irreversible damage to neurons, intracerebral hemorrhage can happen and give rise to rarely cured disability or death. Hemoglobin and its oxidized derivative hemin are released from lysed red blood cells, thus contributing to the secondary injury [44]. Following the initial injury arose from tissue disruption and mass effect of the hematoma, secondary injury motivated by deleterious activities including autophagy becomes a typical symptom of ICH [45]. There is growing evidence also implying that mechanisms included in the interoperable systems of ICH are endoplasmic reticulum (ER), neuronal apoptosis and autophagy etc. [46]. Yet under normal circumstances, only little autophagy can be detected in the mature mammalian brains [11].

When looking back upon the previous studies, whether autophagy, once being activated after subarachnoid hemorrhage (SAH), can positively or negatively affect brain injury still remains to be elusive [47]. Similarly, since the role played by autophagy in ICH is also confusing up till now, many studies have stretched into this field in order to figure out how it affects ICH in details. For instance, Shenet al. conducted in vivo and in vitro experiments in which ICH model in mouse were established and suggested that activated autophagy is possibly to aggravate ICH-induced brain injury in ICH models. They also proved that neuro-damage can be turned into impetus for the NF-κB signaling pathway and consequently enhance inflammation and apoptosis [48]. In order to figure out whether autophagy happens before or after ICH, He et al. carried out a few experiments in male Sprague-Dawley rats and proved that autophagy takes place after ICH and iron serves as a pivotal regulator in ICH-induced autophagy [49]. Noticeably, growing evidence pointed out that iron-mediated toxicity has undeniable function in secondary neuronal injury after ICH [50]. Since premenopausal women enjoy a higher survival rate than men after suffering from ICH, some researchers made great efforts in uncovering the gender difference observed in ICH prognosis and discovered that β-estradiol 3-benzoate (E 2) can inhibit autophagy through estrogen receptor α (ERα) so as to attenuate iron-induced damage in females than in males [51]. Moreover, deferoxamine mesylate (DFO), an iron chelator, has been proved to be able to repair neurological damage in animal models with ICH [50]. These findings all consolidated the exploration of more therapeutic tactics in curing ICH in the future.

As a severe cerebrovascular condition, ICH usually happens at a fast speed and causes spontaneous bleeding into the brain tissues, highlighting the urgent necessity for effective therapeutic strategies of ICH [43]. Data showed that about 20% of ICH patients will undergo neurological dysfunctions to various degrees even though they have received surgeries and long-term hospitalization and rehabilitation are required as well [46]. Generally speaking, treatments for ICH vary from medicine to surgery [43]. In the past, too much spotlights have been shed on how to prevent or inhibit hematoma and its expansion in ICH treatment, and a great number of therapeutic strategies have been put into application including intensive blood pressure lowering, surgical evacuation, endoscopic aspiration with or without lysis, or ultra-hemostatic therapy [50].

Compared with PD and CI, studies focusing on autophagy in ICH embrace a relatively smaller amount. That is to say, much space is still left for the future exploration of autophagy so as to seek more innovative and effective therapeutic approaches to advance ICH treatment.

7. Autophagy in Alzheimer's Disease

Alzheimer’s disease (AD) refers to a series of alternations in cognition and behavior typically observed in patients with a large number of hallmark lesions [52]. As the most common cause of dementia among the aged population, it can make about 35 million people suffered across the world and usually place a heavy economic burden to the whole society [53]. Clinically, AD is presented as a gradual recession of memory as well as cognitive function and ultimately ends in a loss of independence [54]. In terms of its pathogenesis, AD is basically characterized by two neuropathological features: senile plaques (deposits of the β-amyloid peptides outside the cells) and neurofibrillary degeneration (usually evidenced by neurofibrillary tangles) [52]. At molecular level, it is featured by excess amyloid β (Aβ) production and tau hyper-phosphorylation [55].

Accumulated data imply that defective autophagy has an incontestable role in the pathogenesis of senile and neurodegenerative illness, as particular epitomized by AD [56]. A previous study suggested that in AD, autophagy-lysosomal degradation gets interrupted, which means that the process of lysosomal acidification becomes defected and susceptible to the disturbance of diverse factors due to the sophisticated regulation of lysosomal pH [53]. By targeting the rapamycin (mTOR)-dependent pathway or mTOR-independent pathway, autophagy exerts its functions in mammalian animals so as to regulate neuronal homeostasis [56].

Nixon et al. observed that although autophagy induction is stimulated in AD, the degradation of autophagic substances in lysosomes is down-regulated, which enables autophagic vacuoles to accumulate in a massive scale in grossly swollen neurites of suffered neurons [53]. Apart from the truth that accumulated Aβ peptide is common in AD and its metabolism is under the regulation of irregular autophagy in AD, Nilsson & Saido surprisingly observed that autophagy also takes part in the secretion of Aβ, the suppression of which may aggravate neurodegeneration [57]. Cecarini et al. witnessed a crosstalk between the ubiquitin-proteasome system degradation pathway where amyloid-β precursor protein (AβPP) is involved and the autophagy degradation pathway in AD [58]. To be more specific, one previous study elucidated the positive role of chaperone-mediated autophagy damage in aggregating proteins such as α-synuclein or LRRK2 that are important in the occurrence of PD [59]. Hence, these findings have all offered strong support for the indispensable role of autophagy in inducing AD.

In the therapy of AD, how to find neuroprotective agent to protect against neuronal injury is a crucial step. Cai & Yan explored the role of Rapamycin, an inhibitor of mTOR pathway, and concluded that it is capable of facilitating autophagy in which the mutant and toxic protein aggregates can be removed [55]. Thus, Rapamycin is currently treated as a compound of huge therapeutic value in AD. Regarding that the chaperone-mediated autophagy, once being induced, can speed up the removal of pathogenic proteins and benefit cell survival, it has now been treated as a promising therapeutic target of diverse protein-related disorders [59]. Presumably, it may also contribute to the therapy of PD in the future. Besides, emerging evidence supported the link between autophagy function and LRRK2, an enigmatic enzyme, in PD and confirmed the clinical value of LRRK2 in curing PD patients [60].

PD has witnessed an increasing prevalence in line with an aging population. So far, only a small number of researches have involved a probe into the regulation of autophagy in AD. But there is increasing evidence indicating that more and more attention has been drawn to the significance of autophagy in treating AD. In the following study, great efforts are necessitated in order to understand the mechanism and therapeutic value of autophagy in AD.

8. Autophagy in Huntington's Disease

Scientifically speaking, Huntington’s disease (HD) stands for a neurodegenerative disease with inherited feature resulting from an expanded stretch of CAG trinucleotide repeats able to give rise to abnormality and demise of neuronal cells [61]. With regard to its clinical features, patient suffering from HD usually show progressive motor dysfunction, cognitive recession and other psychological troubles [62]. Given that in most neurodegenerative disorders, misfolded proteins are produced and cannot be further degraded by the intracellular protein quality-regulate mechanism, autophagy pathway is gaining a rising status in the study of this field because of its pivotal role in sustaining normal cellular proteostasis in the central nervous system [63]. Previously, autophagy has been shown as a participator in the mutation of huntingtin protein in HD [64]. To be more specific, the occurrence of HD has shown close connection with aberrant macroautophagy [65].

Researches in the past have found that upregulated autophagy was able to improve neurodegenerative disorders resulted from intra-cytosolic aggregate-prone proteins including Huntington’s disease [66]. In HD, mutated huntingtin protein has been acknowledged as a major cause and can interfere with the capability of autophagic vacuoles to distinguish cytosolic cargo [67]. Accumulating evidence has provided strong support for the pathophysiological value of autophagy in HD. For instance, Metzger et al. once mentioned that autophagic pathway is a crucial mechanism contributing to the induction of HD since macroautophagy has been demonstrated to be able to help remove the some long-lived proteins, protein complexes and damaged organells. Besides, it also facilitates the disposal of mutant huntingtin protein which is likely to positively regulate cellular aggregates during HD pathogenesis [65]. Arias et al. also noticed that macroautophagic aberration is positively correlated with the increase in chaperone-mediated autophagy activity during the primary period of HD [67]. Despite those findings above, the underlying mechanism of autophagy in HD and other neurodegenerative illnesses still needs more convincing evidence.

In terms of treating HD, many molecular pathways and therapeutic targets have been suggested in the study of this disorder so far [68]. Yet since there has been no effective illness than can modify therapies of HD, regenerative medicine is seen as of promising value in its treatment at present [62]. The best-characterized drug is rapamycin due to its capability of promoting autophagy and its enhancers (SMERs) can defend against mutant huntingtin fragment toxicity [66]. A previous study also proposed that the autophagy modulation can be taken as a treatment modality to fight against HD and advised that autophagy pathway may become a direct target in the future development of therapeutic strategies of HD after providing some valuable guidelines and caveats [63]. Noteworthy is that some small molecules, after performed with specific chemical screens, can be treated as autophagy enhancers that can be applied for the therapy as well as relevant drug discovery of neurodegenerative disorders including HD [69].

Despite the fact there are a few measures exhibiting great value in detecting the progression of HD, deeper longitudinal studies are still needed to push forward the development of HD therapy [68]. Besides, monitoring the progression of HD with the application of a credible and quantifiable biomarker during it clinical treatment and more insights into its pathophysiological mechanism remain to be hot topics in the coming years.

9. Autophagy in Spinal Cord Injury

As a primary channel through which the brain and the body exchange motor and sensory message, the spinal cord is composed of spinal tracts with longitudinal orientation which surround the central areas (or the gray matter), a place harboring the largest number of spinal neuronal cell bodies [70]. Spinal cord injury (SCI) is a serious and debilitating illness able to give rise to terrible and everlasting neurological deficits caused by the primary mechanical impact followed by secondary tissue injury [71]. Secondary injury response in SCI is featured by a lack of ionic homeostasis, mitochondrial abnormality, glutamate excitotoxicity and microvascular aberration happening right after the primary mechanical injury [72]. When patients entered in the acute stage of SCI injury, autophagy and inflammatory reactions can pave way for the emergence of the secondary injury [71]. Clinical symptoms of SCI include a few types of chronic pain such as peripheral and central neuropathic pain, muscle spasms-induced pain, visceral pain etc. [73]. And traumatic spinal cord injury (TSCI) is typically characterized by a sudden and unexpected occurrence with devastating outcome in human and social terms [74]. The epidemiology of SCI has been involved in extensive studies in the past 40 years [75]. Abundant data indicated that it makes approximately 12,000 to 20,000 young adults in the United States suffered every year and there are currently almost half a million SCI patient across the world [76].

Admittedly, autophagy acts as a core member in the progression of SCI as it shoulders great responsibility in controlling cell death [77]. In order to investigate the connection between autophagy and SCI, Chen et al. established rat SCI models for subsequent experimental procedures and noticed that autophagy was activated after SCI which can be further inhibited by methylprednisolone. They also suggested the possible role of autophagic cell death in inducing neuronal death after spinal cord trauma [78]. Marta et al. made a first trial in determining not only the cellular mechanisms but also the function of autophagy after SCI and proved that autophagy flux was downregulated by lysosomal damage immediately after SCI which further caused pathological accumulation of autophagosomes [76].

The therapy of SCI has drawn extensive attention of researchers from diverse perspectives. Previously, even though it has been observed that neurologic outcomes can be ameliorated by decompressing the setting of SCI at early stage, how early surgical decompression influence patients suffering from severe SCI is still waiting to be investigated [79]. Finnerup & Baastrup conducted a review of the mechanism and management of SCI pain in recent years and put forward that tricyclic antidepressants and pregabalin are supposed to be the first-line treatments to attenuate SCI pain [73]. Nevertheless, there is accumulated evidence putting great emphasis on the role of autophagy in treating SCI. One study demonstrated the emergence of autophagic flux after SIC and therefore concluded that progress in neural recovery can be achieved by inhibiting cell apoptosis [80]. Rapamycin observed as a negative regulator of mTOR signaling, can upregulate autophagy and thus protect the neuronal cells of the central nervous system in a few diseases. It can be applied for the treatment of SCI since it attenuates the neural tissue damage and locomotor injury caused by SCI [81]. Another study also found that rapamycin can promote autophagy via mammalian target of rapamycin inhibition [71]. Hence it can make great contribution to the prognosis of acute SCI through the inhibition of cell apoptosis and serve as an ideal therapeutic agent for its treatment [82]. Besides, valproic acid (VPA) was shown as a neuronal protector in SCI animal models and its participation led to a decrease in autophagy level, which further indicated its therapeutic value in SCI treatment [77].

Pitiful is the fact that apart from surgery for immobilization of the spine and prolonged rehabilitation, valid treatment of SCI is still in short supply [76]. That is to say, there is an urgent need for more randomized trials of therapy in order to push forward the advancement in treating SCI.

10. Conclusion

Autophagy is characterized by a series of cell activities in which cytoplasmic components including organelles and proteins are transferred to the lysosomal compartment for further degradation, and has been confirmed as a pivotal regulator in the maintenance of cellular homeostasis [83]. Autophagy is gaining an increasing status in the study of repair of nerve injury with high clinical value as presented in this study. Especially in the study of its relation with diverse neurodegenerative illnesses including Alzheimer’s disease and Parkinson’s disease, autophagy is targeted in clinical treatment and considered to be of great help in their therapy of these disorders.



11. Implications for future studies

Autophagy is both a conservative defense mechanism and a programmed way of apoptosis for cells. Up till now, the studies of autophagy in nervous system are still in a fledging period. Issues over the signaling pathways and regulatory mechanism of autophagy remain to be further investigated. Particularly, how autophagy exerts impact on neuronal cells in various disorders related to different nervous systems at different stages requires greater efforts to be explained.

Furthermore, a few important problems deserve our attention as well. For example, the selection and establishment of animal models, the selection between autophagic inhibitor and promotor, the mode of administration of medicine, and the combination of in vitro and in vivo experiments etc. should all be taken into consideration in the research on autophagy in nervous system. The activation of autophagy might be a double-edged sword. Once properly activated, it can ensure a lasting stability in metabolism and internal environment by removing aberrant intracellular substances. However, the over-activation of autophagy has been shown to excessively clear the organelles, thus inducing autophagic cell death and severe cell injury. Therefore, how to better make great advantage of autophagy so as to decrease neuronal cell death, protect the healthy cells and improve nerve functions will be taken as a research focus in the future.

Funding: None.

Conflicts of Interest: All authors declare no conflict of interest.

Copyright Statement

©2020 the authors. This article is an open access article licensed under the terms and conditions of the
 CREATIVE COMMONS ATTRIBUTION (CC BY) LICENSE
 (http://creativecommons.org/licenses/by/4.0/).

References

1.Peker N, ozuacik D. Autophagy as a Cellular Stress Response Mechanism in the Nervous System. Journal of Molecular Biology, 2020, 432: 2560–2588.

2.Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochemical Journal, 2012, 441: 523–540.

3.White E. Deconvoluting the context-dependent role for autophagy in cancer. Nature Reviews: Cancer, 2012, 12: 401–410.

4.Deretic V, Saitoh T, kira S. Autophagy in infection, inflammation and immunity. Nature Reviews: Immunology, 2013, 13: 722–737.

5.Puri C, Renna M, Bento CF, Moreau K, Rubinsztein DC. Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell, 2013, 154: 1285–1299.

6.Wang F, Muller S. Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target. Frontiers in Immunology, 2015, 6: 252.

7.Boya P, Reggiori F, Codogno P. Emerging regulation and functions of autophagy. Nature Cell Biology, 2013, 15: 713–720.

8.White E. The role for autophagy in cancer. Journal of Clinical Investigation, 2015, 125: 42–46.

9.Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 2012, 8: 445–544.

10.Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. New England Journal of Medicine, 2013, 368: 651–662.

11.Smith CM, Chen Y, Sullivan ML, Kochanek PM, Clark RS. Autophagy in acute brain injury: feast, famine, or folly? Neurobiology of Disease, 2011, 43: 52–59.

12.Nixon RA. The role of autophagy in neurodegenerative disease. Nature Medicine, 2013, 19: 983–997.

13.Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ. The role of autophagy in Parkinson's disease. Cold Spring Harbor Perspectives in Medicine, 2012, 2: a009357.

14.Abe K, Yamashita T, Takizawa S, Kuroda S, Kinouchi H, et al. Stem cell therapy for cerebral ischemia: from basic science to clinical applications. Journal of Cerebral Blood Flow and Metabolism, 2012, 32: 1317–1331.

15.Parzych KR ,Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxidants and Redox Signaling, 2014, 20: 460–473.

16.Li WW, Li J, Bao JK. Microautophagy: lesser-known self-eating. Cellular and Molecular Life Sciences, 2012, 69: 1125–1136.

17.Jacob JA, Salmani JMM, Jiang Z, Feng L, Song J, et al. Autophagy: An overview and its roles in cancer and obesity. Clinica Chimica Acta, 2017, 468: 85–89.

18.Wirth M, Joachim J, Tooze SA. Autophagosome formation--the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage. Seminars in Cancer Biology, 2013, 23: 301–309.

19.Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology, 2012, 142: 1504–1515 e1503.

20.Shrivastava S, Bhanja Chowdhury J, Steele R, Ray R, Ray RB. Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. Journal of Virology, 2012, 86: 8705–8712.

21.Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy and apoptosis in prostate cancer stem cells via PI3K/Akt/mTOR signaling pathway. Cancer Letters, 2014, 343: 179–189.

22.Wirawan E, Lippens S, Vanden Berghe T, Romagnoli A, Fimia GM, et al. Beclin1: a role in membrane dynamics and beyond. Autophagy, 2012, 8: 6–17.

23.Huang Q, Liu X, Cao C, Lei J, Han D, et al. Apelin-13 induces autophagy in hepatoma HepG2 cells through ERK1/2 signaling pathway-dependent upregulation of Beclin1. Oncology Letters, 2016, 11: 1051–1056.

24.Arduino DM, Esteves AR, Cortes L, Silva DF, Patel B, et al. Mitochondrial metabolism in Parkinson's disease impairs quality control autophagy by hampering microtubule-dependent traffic. Human Molecular Genetics, 2012, 21: 4680–4702.

25.Shen YF, Tang Y, Zhang XJ, Huang KX, Le WD. Adaptive changes in autophagy after UPS impairment in Parkinson's disease. Acta Pharmacologica Sinica, 2013, 34: 667–673.

26.Pitcher JB, Riley AM, Doeltgen SH, Kurylowicz L, Rothwell JC, et al. Physiological evidence consistent with reduced neuroplasticity in human adolescents born preterm. Journal of Neuroscience, 2012, 32: 16410–16416.

27.Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. Journal of Biological Chemistry, 2008, 283: 23542–23556.

28.Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. Journal of Cell Biology, 2008, 183: 795–803.

29.Plowey ED, Cherra SJ, Liu YJ ,Chu CT. Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. Journal of Neurochemistry, 2008, 105: 1048–1056.

30.Beilina A, Cookson MR. Genes associated with Parkinson's disease: regulation of autophagy and beyond. Journal of Neurochemistry, 2016, 139 Suppl 1: 91–107.

31.Sala G, Stefanoni G, Arosio A, Riva C, Melchionda L, et al. Reduced expression of the chaperone-mediated autophagy carrier hsc70 protein in lymphomonocytes of patients with Parkinson's disease. Brain Research, 2014, 1546: 46–52.

32.Li B, Zhang Y, Yuan Y, Chen N. A new perspective in Parkinson's disease, chaperone-mediated autophagy. Parkinsonism & Related Disorders, 2011, 17: 231–235.

33.Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Archives of Neurology, 2010, 67: 1464–1472.

34.Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110: E1817–1826.

35.Liu J, Chen M, Wang X, Wang Y, Duan C, et al. Piperine induces autophagy by enhancing protein phosphotase 2A activity in a rotenone-induced Parkinson's disease model. Oncotarget, 2016, 7: 60823–60843.

36.Shi R, Weng J, Zhao L, Li XM, Gao TM, et al. Excessive autophagy contributes to neuron death in cerebral ischemia. CNS Neuroscience & Therapeutics, 2012, 18: 250–260.

37.Sabri M, Lass E, Macdonald RL. Early brain injury: a common mechanism in subarachnoid hemorrhage and global cerebral ischemia. Stroke Research and Treatment, 2013, 2013: 394036.

38.Wang P, Guan YF, Du H, Zhai QW, Su DF, et al. Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy, 2012, 8: 77–87.

39.Zhang X, Yan H, Yuan Y, Gao J, Shen Z, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy, 2013, 9: 1321–1333.

40.Gao L, Jiang T, Guo J, Liu Y, Cui G, et al. Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats. PloS One, 2012, 7: e46092.

41.Lou YL, Guo F, Liu F, Gao FL, Zhang PQ, et al. miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia. Molecular and Cellular Biochemistry, 2012, 370: 45–51.

42.Balduini W, Carloni S, Buonocore G. Autophagy in hypoxia-ischemia induced brain injury. Journal of Maternal-Fetal & Neonatal Medicine, 2012, 25 Suppl 1: 30–34.

43.Wu Z, Zou X, Zhu W, Mao Y, Chen L, et al. Minocycline is effective in intracerebral hemorrhage by inhibition of apoptosis and autophagy. Journal of the Neurological Sciences, 2016, 371: 88–95.

44.Zille M, Karuppagounder SS, Chen Y, Gough PJ, Bertin J, et al. Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke, 2017, 48: 1033–1043.

45.Selim M, Sheth KN. Perihematoma edema: a potential translational target in intracerebral hemorrhage? Translational Stroke Research, 2015, 6: 104–106.

46.Duan X, Wen Z, Shen H, Shen M, Chen G. Intracerebral Hemorrhage, Oxidative Stress, and Antioxidant Therapy. Oxidative Medicine and Cellular Longevity, 2016, 2016: 1203285.

47.Jing CH, Wang L, Liu PP, Wu C, Ruan D, et al. Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. Neuroscience, 2012, 213: 144–153.

48.Shen X, Ma L, Dong W, Wu Q, Gao Y, et al. Autophagy regulates intracerebral hemorrhage induced neural damage via apoptosis and NF-kappaB pathway. Neurochemistry International, 2016, 96: 100–112.

49.He Y, Wan S, Hua Y, Keep RF, Xi G. Autophagy after experimental intracerebral hemorrhage. Journal of Cerebral Blood Flow and Metabolism, 2008, 28: 897–905.

50.Selim M, Yeatts S, Goldstein JN, Gomes J, Greenberg S, et al. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke, 2011, 42: 3067–3074.

51.Chen CW, Chen TY, Tsai KL, Lin CL, Yokoyama KK, et al. Inhibition of autophagy as a therapeutic strategy of iron-induced brain injury after hemorrhage. Autophagy, 2012, 8: 1510–1520.

52.Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathologica, 2012, 123: 1–11.

53.Wolfe DM, Lee JH, Kumar A, Lee S, Orenstein SJ, et al. Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification. European Journal of Neuroscience, 2013, 37: 1949–1961.

54.Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. New England Journal of Medicine, 2012, 367: 795–804.

55.Cai Z, Yan LJ. Rapamycin, Autophagy, and Alzheimer's Disease. Journal of Biochemical and Pharmacological Research, 2013, 1: 84–90.

56.Zhu XC, Yu JT, Jiang T, Tan L. Autophagy modulation for Alzheimer's disease therapy. Molecular Neurobiology, 2013, 48: 702–714.

57.Nilsson P, Saido TC. Dual roles for autophagy: degradation and secretion of Alzheimer's disease Abeta peptide. Bioessays, 2014, 36: 570–578.

58.Cecarini V, Bonfili L, Cuccioloni M, Mozzicafreddo M, Rossi G, et al. Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease. Biochimica et Biophysica Acta, 2012, 1822: 1741–1751.

59.Xilouri M, Stefanis L. Chaperone mediated autophagy to the rescue: A new-fangled target for the treatment of neurodegenerative diseases. Molecular and Cellular Neurosciences, 2015, 66: 29–36.

60.Atashrazm F, Dzamko N. LRRK2 inhibitors and their potential in the treatment of Parkinson's disease: current perspectives. Clinical Pharmacology: Advances and Applications, 2016, 8: 177–189.

61.Consortium HDi. Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell, 2012, 11: 264–278.

62.An MC, Zhang N, Scott G, Montoro D, Wittkop T, et al. Genetic correction of Huntington's disease phenotypes in induced pluripotent stem cells. Cell Stem Cell, 2012, 11: 253–263.

63.Cortes CJ, La Spada AR. The many faces of autophagy dysfunction in Huntington's disease: from mechanism to therapy. Drug Discovery Today, 2014, 19: 963–971.

64.Sarkar S, Rubinsztein DC. Huntington's disease: degradation of mutant huntingtin by autophagy. FEBS Journal, 2008, 275: 4263–4270.

65.Metzger S, Saukko M, Van Che H, Tong L, Puder Y, et al. Age at onset in Huntington's disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Human Genetics, 2010, 128: 453–459.

66.Floto RA, Sarkar S, Perlstein EO, Kampmann B, Schreiber SL, et al. Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington's disease models and enhance killing of mycobacteria by macrophages. Autophagy, 2007, 3: 620–622.

67.Koga H, Martinez-Vicente M, Arias E, Kaushik S, Sulzer D, et al. Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease. Journal of Neuroscience, 2011, 31: 18492–18505.

68.Ha AD, Fung VS. Huntington's disease. Current Opinion in Neurology, 2012, 25: 491–498.

69.Sarkar S. Chemical screening platforms for autophagy drug discovery to identify therapeutic candidates for Huntington's disease and other neurodegenerative disorders. Drug Discovery Today: Technologies, 2013, 10: e137–144.

70.Committee M, Burns S, Biering-Sorensen F, Donovan W, Graves DE, et al. International standards for neurological classification of spinal cord injury, revised 2011. Topics in Spinal Cord Injury Rehabilitation, 2012, 18: 85–99.

71.Chen HC, Fong TH, Hsu PW, Chiu WT. Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection. Journal of Surgical Research, 2013, 179: e203–210.

72.Bains M, Hall ED. Antioxidant therapies in traumatic brain and spinal cord injury. Biochimica et Biophysica Acta, 2012, 1822: 675–684.

73.Finnerup NB, Baastrup C. Spinal cord injury pain: mechanisms and management. Current Pain and Headache Reports, 2012, 16: 207–216.

74.Lee BB, Cripps RA, Fitzharris M, Wing PC. The global map for traumatic spinal cord injury epidemiology: update 2011, global incidence rate. Spinal Cord, 2014, 52: 110–116.

75.Devivo MJ. Epidemiology of traumatic spinal cord injury: trends and future implications. Spinal Cord, 2012, 50: 365–372.

76.Lipinski MM, Wu J. Modification of autophagy-lysosomal pathway as a neuroprotective treatment for spinal cord injury. Neural Regeneration Research, 2015, 10: 892–893.

77.Hao HH, Wang L, Guo ZJ, Bai L, Zhang RP, et al. Valproic acid reduces autophagy and promotes functional recovery after spinal cord injury in rats. Neuroscience Bulletin, 2013, 29: 484–492.

78.Chen HC, Fong TH, Lee AW, Chiu WT. Autophagy is activated in injured neurons and inhibited by methylprednisolone after experimental spinal cord injury. Spine, 2012, 37: 470–475.

79.Fehlings MG, Vaccaro A, Wilson JR, Singh A, Cadotte DW, et al. Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PloS One, 2012, 7: e32037.

80.Hou H, Zhang L, Zhang L, Tang P. Acute spinal cord injury in rats should target activated autophagy. Journal of Neurosurgery: Spine, 2014, 20: 568–577.

81.Sekiguchi A, Kanno H, Ozawa H, Yamaya S, Itoi E. Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. Journal of Neurotrauma, 2012, 29: 946–956.

82.Wang ZY, Liu WG, Muharram A, Wu ZY, Lin JH. Neuroprotective effects of autophagy induced by rapamycin in rat acute spinal cord injury model. Neuroimmunomodulation, 2014, 21: 257–267.

83.Dong Y, Wang S, Zhang T, Zhao X, Liu X, et al. Ascorbic acid ameliorates seizures and brain damage in rats through inhibiting autophagy. Brain Research, 2013, 1535: 115–123.





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