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.

Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

“…Considering the results, we propose that intraneuronal A␤ in AD does not originate from internalization of secreted peptide but from impairments in ECE activity. As alterations in the endosomal/lysosomal and autophagic pathways are observed early in the AD course and coincide with iA␤ accumulation (6,14,47), they could represent an underlying cause of ECE dysfunction and increase in iA␤.…”

Mechanisms of Action of Bcl-2 Family Proteins

“…However, it is increasingly apparent that the ER is the site of many important processes that determine cell death and survival in which the Bcl-2 family is intimately involved. Aside from controlling calcium flux (Rong et al 2009) and regulating the activity of Beclin-1 to initiate autophagy (see Mah and Ryan 2012;Nixon and Yang 2012), other death pathways are also inhibited by Bcl-2 at the ER (Germain et al 2002). Beyond this, there is also evidence that a portion of the antiapoptotic activity of Bcl-2/ Bcl-XL does not depend on binding to and inhibiting the other two proapoptotic families (Minn et al 1999).…”

Downregulation of B-cell lymphoma/leukemia-2 by overexpressed microRNA 34a enhanced titanium dioxide nanoparticle-induced autophagy in BEAS-2B cells

“…44 Autophagic recycling, therefore, yields simple metabolites for use in cell growth or bioenergetics, and can destroy damaged structures to prevent inflammatory, infectious, neurodegenerative, and neoplastic disorders, and deregulation of this pathway has been implicated in the pathogenesis of numerous human diseases. 22,33,45 The process of autophagy in BEAS-2B cells exposed to TNPs was also presented in the TEM images, which was similar to the TNP-induced autophagy noted in keratinocytes. 26 Besides, to further monitor autophagy triggered by TNPs in BEAS-2B cells, MDC staining and LC3-I/LC3-II conversion were employed according to the guidelines.…”

“…19,20 Autophagy, therefore, serves as a natural and essential defense mechanism against inflammatory, infectious, neurodegenerative, and neoplastic disorders, and deregulation of this pathway has been implicated in the pathogenesis of numerous human diseases. [21][22][23][24] Activation of autophagy was considered as an attempt for a cell to maintain cellular homeostasis by sequestering and degrading exogenous materials entered into the cytoplasm. However, the toxicological consequence of autophagy dysfunction is regarded as a potential mechanism of cell death.…”