Autophagy and neuronal cell death in neurological disorders.
ABSTRACT 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.
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- "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. "
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 · 2.92 Impact Factor
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- "Until we identify the reason for protein aggregation in sporadic forms of these diseases, eliciting proteotoxicity with proteasome inhibition in cellular models or by direct infusion into the brain appears to be a reasonable and practical model of protein misfolding stress (Fornai et al. 2006; Pan et al. 2008; Vernon et al. 2010; Zhang et al. 2012). Another form of proteotoxicity in neurodegenerative disorders is the presence of autophagic stress (Nixon and Yang 2012; Son et al. 2012; Salminen et al. 2013). Autophagy by the lysosome is an alternative means to clear cellular debris such as misfolded proteins, and can be mobilized in self-defense when the proteasome is inhibited (Iwata et al. 2005; Ding et al. 2007; Rubinsztein et al. 2007; Janen et al. 2010; Wong and Cuervo 2010). "
ABSTRACT: Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.Dose-Response 01/2014; 12(1):24-56. DOI:10.2203/dose-response.13-016.Leak · 1.23 Impact Factor
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- "Since then, neurofibrillary tangles have been established to be comprised of hyperphosphorylated tau protein, whereas plaques being represented by dense aggregates of Ab peptide (its major Ab 1e40 and Ab 1e42 forms and N-terminally truncated fragments) and other proteins (Iwatsubo et al., 1994; Thal et al., 2006). Later ultrastructural studies demonstrated that swollen and dystrophic neuritis, in addition to hyperphosphorylated tau, are also enriched with autophagosomes and lysosomes, containing an array of cathepsins (Nixon and Yang, 2012; Suzuki and Terry, 1967). The key role of autophagosomes and lysosomes in Ab proteolysis in neurons has become more evident recently, with reports documenting their enrichment also with Ab peptide (LaFerla et al., 2007; Nixon et al., 2008). "
ABSTRACT: Cholinergic basal forebrain (BF) neurons source one of the largest modulator systems of the brain, supplying acetylcholine to the entire cerebral mantle. Ample evidence suggests a causal link between the depletion of cortical acetylcholine and the selective disruption of cognitive functions in the course of aging and Alzheimer's disease (AD). A distinctive yet underappreciated feature of BF cholinergic neurons is their enrichment with the p75 neurotrophin receptor (p75(NTR)), which is also recognized as a high-affinity acceptor for the amyloid-β (Aβ) peptide. Herein, we critically overview the emerging data, which suggest the relevance of p75(NTR)-mediated uptake of Aβ followed by its degradation in lysosomes of BF cholinergic neurons for the homeostasis and clearance of this peptide from the cerebral cortex. We propose that via such a unique arrangement, cholinergic neurons afford their functional targets with an efficient molecular "drain" for Aβ. This process is suggested as the proximal cause for the greater "wear and tear" of the BF cholinergic system during aging and especially AD.Neurobiology of aging 06/2013; 34(11). DOI:10.1016/j.neurobiolaging.2013.05.005 · 4.85 Impact Factor