Article

Autophagy and neuronal cell death in neurological disorders.

Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York 10962.
Cold Spring Harbor perspectives in biology (Impact Factor: 8.23). 09/2012; 4(10). DOI: 10.1101/cshperspect.a008839
Source: PubMed

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. "
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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). "
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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). "
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