The Role of Autophagy in Age-Related Neurodegeneration
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Neurosignals
(Impact Factor: 2).
02/2008; 16(1):75-84. DOI: 10.1159/000109761
Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. In many cases, these proteinaceous deposits are composed of ubiquitin conjugates, suggesting a failure in the clearance of proteins targeted for degradation. The 2 principal routes of intracellular protein catabolism are the ubiquitin proteasome system and the autophagy-lysosome system (autophagy). Both of these degradation pathways have been implicated as playing important roles in the pathogenesis of neurodegenerative disease. Here we describe autophagy and review the evidence suggesting that impairment of autophagy contributes to the initiation or progression of age-related neurodegeneration. We also review recent evidence indicating that autophagy may be exploited to remove toxic protein species, suggesting novel strategies for therapeutic intervention for a class of diseases for which no effective treatments presently exist.
Available from: Rafael Leon
- "The most representative are abnormal protein aggregation (Ross & Poirier, 2005), proteasomal (Halliwell, 2006) or autophagic dysfunction (McCray & Taylor, 2008), inflammation (Zipp & Aktas, 2006), neuronal apoptosis (Okouchi et al., 2007), oxidative stress (Andersen, 2004), mitochondrial dysfunction (Lin & Beal, 2006), and abnormal interactions between neurons and glia that accentuate the inflammatory status (Carnevale et al., 2007). Among them, mitochondrial dysfunction, reactive gliosis and oxidative damage to lipids, proteins and DNA, have been widely described in AD (Butterfield et al., 2001; Shaftel et al., 2008), PD (Alam et al., 1997; Clements et al., 2006), HD (Browne & Beal, 2006), ALS (Goodall & Morrison, 2006), and ischemic stroke (Olmez & Ozyurt, 2012). "
[Show abstract] [Hide abstract]
ABSTRACT: Neurodegenerative diseases (NDDs) are predicted to be the biggest health concern in this century and the second leading cause of death by 2050. The main risk factor of these diseases is aging, and as the aging population in Western societies is increasing, the prevalence of these diseases is augmenting exponentially. Despite the great efforts to find a cure, current treatments remain ineffective or have low efficacy. Increasing lines of evidence point to exacerbated oxidative stress, mitochondrial dysfunction and chronic neuroinflammation as common pathological mechanisms underlying neurodegeneration. We will address the role of the nuclear factor E2-related factor 2 (Nrf2) as a potential target for the treatment of NDDs. The Nrf2-ARE pathway is an intrinsic mechanism of defence against oxidative stress. Nrf2 is a transcription factor that induces the expression of a great number of cytoprotective and detoxificant genes. There are many evidences that highlight the protective role of the Nrf2-ARE pathway in neurodegenerative conditions, as it reduces oxidative stress and neuroinflammation. Therefore, the Nrf2 pathway is being increasingly considered a therapeutic target for NDDs. Herein we will review the deregulation of the Nrf2 pathway in different NDDs and the recent studies with Nrf2 inducers as "proof-of-concept" for the treatment of those devastating pathologies.
Available from: Ying-Hsien Kao
- "By contrast, the increased contents of autophagy markers, Atg5 and LC3, are recently evidenced in RPE/choroids in aged mice as well as in drusen in the retina of old eyes of AMD patients (Wang et al., 2009b), implicating the involvement of autophagic dysfunction in the AMD pathogenesis . The function of autophagy machinery in aged cells has been previously proposed to be impaired by an intracellular burden of ROS-damaged macromolecules and organelles (McCray and Taylor, 2008). In the context of MGO-related cytotoxicity in ocular component cells, to date MGO exposure is only known to result in apoptosis of retinal pericytes (Kim et al., 2004) and lens epithelial cells (Kim et al., 2012). "
[Show abstract] [Hide abstract]
ABSTRACT: Methylglyoxal (MGO), a glycolytic metabolite, induces oxidative injury and apoptotic cell death that play a pathogenetic role in age-related macular degeneration (AMD). This study examined the impact of MGO on cell proliferation and autophagy flux in retinal pigment epithelium (RPE) ARPE-19 cells and elucidated the underlying mechanism. Short-term MGO exposure suppressed cell proliferation without induction of apoptotic cell death, increased production of reactive oxygen species, and potentiated H2O2-exhibited cytotoxicity in ARPE-19 cells. Conversely, pretreatment with N-acetylcysteine, a ROS scavenger, and aminoguanidine, an MGO blocker, prevented MGO-induced growth retardation. MGO significantly enhanced autophagy flux and increased intracellular accumulation of autophagosomes, which was functionally confirmed by addition of autophagy enhancer or inhibitors. Signaling kinetic observation indicated that MGO remarkably triggered phosphorylation of Akt, ERK1/2, p38 MAPK, and JNK1/2. Blockade of kinase activity demonstrated that the hyperphosphorylation of Akt, ERK1/2, JNK, and p38 MAPK were all involved in the MGO-enhanced autophagy and growth-arresting effect in ARPE-19 cells. Moreover, pretreatment with autophagic flux inhibitors including 3-methyladenine, bafilomycin A, and chloroquine effectively ameliorated MGO- but not H2O2-mediated ARPE-19 cytotoxicity. In conclusion, modulation of autophagy flux activity by using autophagic or kinase inhibitors may be an applicable modality to treat AMD.
Copyright © 2015. Published by Elsevier Ltd.
Available from: Adelaide Fernandes
- "Several neurodegenerative diseases are characterized by the formation of intracellular protein aggregates in affected brain regions, indicating a failure of protein degradation system (McCray and Taylor, 2008). Autophagy is a stress-induced catabolic process responsible for the degradation of long-lived proteins and damaged organelles (Levine and Klionsky, 2004) that was shown to decline with aging (Bergamini, 2006) and to determine cell and individual lifespan (Juhasz et al., 2007). "
[Show abstract] [Hide abstract]
ABSTRACT: Age-related neurodegenerative diseases have been associated with chronic neuroinflammation and microglia activation. However, cumulative evidence supports that inflammation only occurs at an early stage once microglia change the endogenous characteristics with ageing and switch to irresponsive/senescent and dystrophic phenotypes with disease progression. Thus, it will be important to have the means to assess the role of reactive and aged microglia when studying advanced brain neurodegeneration processes and age-associated related disorders. Yet, most studies are done with microglia from neonates since there are no adequate means to isolate degenerating microglia for experimentation. Indeed, only a few studies report microglia isolation from aged animals, using either short-term cultures or high concentrations of mitogens in the medium, which trigger microglia reactivity. The purpose of this study was to develop an experimental process to naturally age microglia after isolation from neonatal mice and to characterize the cultured cells at 2 days in vitro (DIV), 10 DIV and 16 DIV. We found that 2 DIV (young) microglia had predominant amoeboid morphology and markers of stressed/reactive phenotype. In contrast, 16 DIV (aged) microglia evidenced ramified morphology and increased metalloproteinase (MMP)-2 activation, as well as reduced MMP-9, glutamate release and nuclear factor kappa-B activation, in parallel with decreased expression of Toll-like receptor (TLR)-2 and TLR-4, capacity to migrate and phagocytose. These findings together with the reduced expression of microRNA (miR)-124, and miR-155, decreased autophagy, enhanced senescence associated beta-galactosidase activity and elevated miR-146a expression, are suggestive that 16 DIV cells mainly correspond to irresponsive/senescent microglia. Data indicate that the model represent an opportunity to understand and control microglial aging, as well as to explore strategies to recover microglia surveillance function.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.