Autophagy and Neuronal Cell Death in Neurological Disorders
Autophagy is implicated in the pathogenesis of major neurodegenerative disorders although concepts about how it influences these diseases are still evolving. Once proposed to be mainly an alternative cell death pathway, autophagy is now widely viewed as both a vital homeostatic mechanism in healthy cells and as an important cytoprotective response mobilized in the face of aging- and disease-related metabolic challenges. In Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and other diseases, impairment at different stages of autophagy leads to the buildup of pathogenic proteins and damaged organelles, while defeating autophagy's crucial prosurvival and antiapoptotic effects on neurons. The differences in the location of defects within the autophagy pathway and their molecular basis influence the pattern and pace of neuronal cell death in the various neurological disorders. Future therapeutic strategies for these disorders will be guided in part by understanding the manifold impact of autophagy disruption on neurodegenerative diseases.
Available from: Ju-hyun Lee
- "PS1 dysfunction is therefore likely to contribute in multiple ways to AD pathogenesis by altering Abeta clearance, production, and oligomerization (Nixon, 2007) and corrupting diverse lysosomal functions via the massive buildup of incompletely degraded autophagic substrates in lysosomes, a characteristic feature of the neuritic dystrophy in AD (Nixon and Yang, 2012). Lysosomal dysfunction in neurons is closely tied to neurodegeneration and cell death mechanisms ( Cesen et al., 2012; Nixon and Yang, 2012). Growing genetic and biochemical evidence implicates dysfunction of the endosomal-lysosomal and autophagic lysosomal pathways in the pathogenesis of a number of neurodegenerative disorders, including AD, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) (Frakes et al., 2014; Ghavami et al., 2014; Menzies et al., 2015; Nixon, 2013). "
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ABSTRACT: Presenilin 1 (PS1) deletion or Alzheimer's disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO) cells induces abnormal Ca(2+) efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca(2+). In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca(2+) homeostasis, but correcting lysosomal Ca(2+) deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca(2+) homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Cell Reports 08/2015; 12(9). DOI:10.1016/j.celrep.2015.07.050 · 8.36 Impact Factor
- "Impaired autophagy as a major contributing factor is implicated in the pathogenesis of multiple neurodegenerative disorders (Nixon and Yang, 2012). Although autophagy has been associated with SCZ (Merenlender-Wagner et al., 2013), no experimental evidence has been linked to the pathogenesis of any SCZ risk gene. "
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ABSTRACT: Schizophrenia (SCZ) is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 (dystrobrevin-binding protein 1) gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-1C isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyrus, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-1-deficient sandy (sdy) mice (a mouse model of SCZ) is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3-II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-1C. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells of sdy mice. In addition, overexpression of dysbindin-1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin-1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.
Copyright © 2014 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.
Journal of Genetics and Genomics 01/2015; 42(1):1-8. DOI:10.1016/j.jgg.2014.12.001 · 3.59 Impact Factor
- "In the process of autophagy, autophagosomes (twomembraned and containing degenerating cytoplasmic organelles or parts of the cytoplasm) are finally delivered to lysosomes for bulk degradation  . A basal level of autophagy is a homeostatic cytoprotective mechanism; however, the autophagy dysfunction can lead to severe pathological states, such as neurodegenerative diseases, cardiomyopathy, and particularly cancer  . "
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ABSTRACT: Silica nanoparticles (SNPs) are becoming favorable carriers for drug delivery or gene therapy, and in turn, the toxic effect of SNPs on biological systems is gaining attention. Currently, autophagy is recognized as an emerging toxicity mechanism triggered by nanomaterials, yet there have been scarcely research about the mechanisms of autophagy and autophagic cell death associated with SNPs. In this study, we verified the activation of SNPs-induced autophagy via the MDC-staining and LC3-I/LC3-II conversion, resulted in a dose-dependent manner. The typically morphological characteristics (autophagosomes and autolysosomes) of the autophagy process were observed in TEM ultrastructural analysis. In addition, the autophagic cell death was evaluated by cellular co-staining assay. And the underlying mechanisms of autophagy and autophagic cell death were performed using the intracellular ROS detection, autophagy inhibitor and ROS scavenger. Results showed that the elevated ROS level was in line with the increasing of autophagy activation, while both the 3-MA and NAC inhibitors effectively suppressed the autophagy and cell death induced by SNPs. In summary, our findings demonstrated that the SNPs-induced autophagy and autophagic cell death were triggered by the ROS generation in HepG2 cells, suggesting that exposure to SNPs could be a potential hazardous factor for maintaining cellular homeostasis.
Journal of hazardous materials 04/2014; 270:176–186. DOI:10.1016/j.jhazmat.2014.01.028 · 4.53 Impact Factor
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