Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

Yang, Danjing; Zhu, Liang; Ren, Jie; Ma, Rongjie; Zhu, Hongwen; Xu, Jianxiang

doi:10.1007/s12264-015-1541-9

Cited by 11 publications

(11 citation statements)

References 48 publications

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“…The occurrence of defective autophagy in ALS was demonstrated for the first time in the last decade (Fornai et al, 2008a , b ); and it was progressively validated through a growing number of studies (Pasquali et al, 2009 ; Ferrucci et al, 2010 ; Otomo et al, 2012 ; Shimada et al, 2012 ; Wang et al, 2012 ; Castillo et al, 2013 ; Ikenaka et al, 2013 ; Barmada et al, 2014 ; Cheng et al, 2015 ; Lee et al, 2015 ; Philips and Rothstein, 2015 ; Xiao et al, 2015 ; Yang et al, 2015 ) up to the very recent confirmative work by Xie et al ( 2015a , b ). This evidence was reviewed in this issue by Ruffoli et al ( 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis

Natale

Lenzi

Lazzeri

et al. 2015

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is characterized by massive loss of motor neurons. Data from ALS patients and experimental models indicate that mitochondria are severely damaged within dying or spared motor neurons. Nonetheless, recent data indicate that mitochondrial preservation, although preventing motor neuron loss, fails to prolong lifespan. On the other hand, the damage to motor axons plays a pivotal role in determining both lethality and disease course. Thus, in the present article each motor neuron compartment (cell body, central, and peripheral axons) of G93A SOD-1 mice was studied concerning mitochondrial alterations as well as other intracellular structures. We could confirm the occurrence of ALS-related mitochondrial damage encompassing total swelling, matrix dilution and cristae derangement along with non-pathological variations of mitochondrial size and number. However, these alterations occur to a different extent depending on motor neuron compartment. Lithium, a well-known autophagy inducer, prevents most pathological changes. However, the efficacy of lithium varies depending on which motor neuron compartment is considered. Remarkably, some effects of lithium are also evident in wild type mice. Lithium is effective also in vitro, both in cell lines and primary cell cultures from the ventral spinal cord. In these latter cells autophagy inhibition within motor neurons in vitro reproduced ALS pathology which was reversed by lithium. Muscle and glial cells were analyzed as well. Cell pathology was mostly severe within peripheral axons and muscles of ALS mice. Remarkably, when analyzing motor axons of ALS mice a subtotal clogging of axoplasm was described for the first time, which was modified under the effects of lithium. The effects induced by lithium depend on several mechanisms such as direct mitochondrial protection, induction of mitophagy and mitochondriogenesis. In this study, mitochondriogenesis induced by lithium was confirmed in situ by a novel approach using [2-3H]-adenosine.

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Section: Introductionmentioning

confidence: 99%

Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis

Natale

Lenzi

Lazzeri

et al. 2015

Front. Cell. Neurosci.

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“…Dysregulation of autophagy in cerebral ischemia [36][37][38] Motor neuron disease Defect SQSTM1, KDEL, DCTN Lysosome-associated membrane proteins and LC3B-I is abnormally upregulated in tissues 39,40 (Continues) T A B L E 1 (Continued) Anatomy of the systems Accumulation of amyloid-β protein 38,41,42 Epilepsy Defect Foxo3a, MTOR, ATG12, ATG5, ATG16…”

Section: Congenital Myopathiesmentioning

confidence: 99%

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

Sui

Zhang

et al. 2019

Medicinal Research Reviews

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Autophagy is central to the maintenance of intracellular homeostasis across species. Accordingly, autophagy disorders are linked to a variety of diseases from the embryonic stage until death, and the role of autophagy as a therapeutic target has been widely recognized. However, autophagy‐associated therapy for human diseases is still in its infancy and is supported by limited evidence. In this review, we summarize the landscape of autophagy‐associated diseases and current autophagy modulators. Furthermore, we investigate the existing autophagy‐associated clinical trials, analyze the obstacles that limit their progress, offer tactics that may allow barriers to be overcome along the way and then discuss the therapeutic potential of autophagy modulators in clinical applications.

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“…In this special issue, "Autophagy in Neural Function [15,[17][18][19][20][21][22][23][24][25][26][27][28] .…”

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confidence: 99%

“…It is becoming clearer that autophagy dysregulation plays an important role in several major neurological and psychological disorders [15,[22][23][24][25][26][27][28] . In this special issue, Dr. Chen's group give an in-depth review on the role of mitophagy in ischemic brain injury [22] .…”

mentioning

confidence: 99%

“…Le's lab [15] and this is ameliorated by overexpression of histone deacetylase 6, an adaptor protein promoting autophagosome-lysosome fusion. CHIP, an E3 ligase, is also considered to be an important player in regulating autophagic fl ux associated with ALS and other motor neuron diseases [26] . In addition to these neurological diseases, autophagy dysregulation is believed to contribute to the pathophysiology of major depressive disorder and many anti-depressants are autophagy modulators [27] .…”

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confidence: 99%

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Selective role of autophagy in neuronal function and neurodegenerative diseases

Rui

2015

Neurosci. Bull.

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·Editorial·Proteostasis is critical for neuronal maintenance and survival, and its imbalance leads to neurodegeneration with the hallmark of protein misfolding and aggregation [1] .Macroautophagy becomes a major route for the clearance of protein aggregates that are normally poor substrates for the proteasome, the other protein quality-control machinery [2] . As a fl ux process, macroautophagy (hereafter referred to as autophagy) involves the formation of the autophagosome, a double-membrane vesicle for engulfi ng unwanted cellular components such as protein aggregates, and the fusion of autophagosomes with lysosomes that contain many potent proteases for fi nal degradation [3] .In the past decades, the mechanism of autophagy has been intensively studied under starvation conditions. Autophagy is a hierarchical process involving the activation of ULK1, the initiating kinase, and many downstream events such as Beclin 1 complex activation and LC3 lipidation [3] . It has been well established that, during amino-acid starvation, mTOR, the master nutrient sensor, dissociates from and in turn activates ULK1 kinase [4] .Interestingly, upon energy starvation such as glucose depletion, the main energy sensor AMPK activates ULK1 through antagonizing mTOR-mediated ULK1 inhibitory phosphorylation [5] . It is generally believed that starvation induces non-selective autophagy that targets non-essential cellular components for degradation to provide building blocks for cellular survival in unfavorable conditions.In comparison with the well-characterized starvationinduced nonselective autophagy, the molecular mechanism of selective autophagy is largely unknown [6] . Selective autophagy is a comprehensive term that can be classifi ed into many different types such as aggrephagy, mitophagy, and lipophagy [7] . In particular, aggrephagy plays an important role in neuronal survival, as neurons are nondividing cells and cannot overcome cellular toxicity induced by protein aggregates through dilution effects. Therefore, aggrephagy becomes essential for neurons to preserve proteostasis. However, the underlying mechanism is yet to be uncovered. Recently, Huntingtin, the Huntington's disease gene product, was identifi ed as a scaffold protein for selective autophagy including aggrephagy, mitophagy, and lipophagy in mammalian cells, paving the way for further investigation in this emerging young field [8] . In addition, cargo receptor proteins such as p62 and NBR1 bring cargos to autophagosomes by interacting with the autophagosomal protein LC3 [9] . As both p62 and NBR1 contain ubiquitin-binding domains, the cargos modifi ed by lineage-specific ubiquitin play an important role in cargo recognition in selective autophagy. For instance, ubiquitin K63-modified substrates preferentially bind to p62 for autophagic degradation [10] .Selective autophagy has been linked to a variety of human diseases including but not limited to neurodegeneration and cancer [11] . For example, tau protein, implicated in Alzheimer's disease (AD), was shown to be ...

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Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

Cited by 11 publications

References 48 publications

Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis

Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

Selective role of autophagy in neuronal function and neurodegenerative diseases

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