Therapeutic implication of autophagy in neurodegenerative diseases

Abstract

Autophagy, a catabolic process necessary for the maintenance of intracellular homeostasis, has recently been the focus of numerous human diseases and conditions, such as aging, cancer, development, immunity, longevity, and neurodegeneration. However, the continued presence of autophagy is essential for cell survival and dysfunctional autophagy is thought to speed up the progression of neurodegeneration. The actual molecular mechanism behind the progression of dysfunctional autophagy is not yet fully understood. Emerging evidence suggests that basal autophagy is necessary for the removal of misfolded, aggregated proteins and damaged cellular organelles through lysosomal mediated degradation. Physiologically, neurodegenerative disorders are related to the accumulation of amyloid β peptide and α-synuclein protein aggregation, as seen in patients with Alzheimer’s disease and Parkinson’s disease, respectively. Even though autophagy could impact several facets of human biology and disease, it generally functions as a clearance for toxic proteins in the brain, which contributes novel insight into the pathophysiological understanding of neurodegenerative disorders. In particular, several studies demonstrate that natural compounds or small molecule autophagy enhancer stimuli are essential in the clearance of amyloid β and α-synuclein deposits. Therefore, this review briefly deliberates on the recent implications of autophagy in neurodegenerative disorder control, and emphasizes the opportunities and potential therapeutic application of applied autophagy.

Cellular and molecular mechanisms involved in the resolution of innate leukocyte inflammation

“…In addition to its direct role as a negative regulator of inflammation through its effects on TLR and IL-1R signaling, Tollip may contribute to cellular homeostasis by facilitating endosomal trafficking and lysosomal fusion. 29,45,46 Tollip was found to be associated with endosomes and recruits target of Myb protein 1 and ubiquitinated proteins. 45 Tollip-deficient macrophages exhibit an accumulation of p62 as well as a decrease in endosomal acidity compared to wild-type cells.…”

“…45 Tollip-deficient macrophages exhibit an accumulation of p62 as well as a decrease in endosomal acidity compared to wild-type cells. 29 The expression of key lysosomal fusion molecules was also compromised in Tollip-deficient cells and tissues. 46 At the pathological level, ApoE −/− Tollip −/− mice had an increase in atherosclerosis with atherosclerotic plaques containing increased amounts of p62, suggesting a defect in lipophagy (a specialized form of autophagy involved in lipid degradation) in vivo.…”

“…Defects in the autophagy protein beclin1 have been implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntingtin's disease . Further studies that thoroughly explore the regulation of autophagy and its involvement with inflammation resolution may hold promise for developing effective therapies to treat diverse inflammatory diseases …”

“…Tollip has also been shown to be a negative regulator of TLR2 and TLR4 signaling in a similar fashion (inhibiting IRAK‐1) and has been found to contribute to IL‐1R degradation via the endolysosomal pathway. In addition to its direct role as a negative regulator of inflammation through its effects on TLR and IL‐1R signaling, Tollip may contribute to cellular homeostasis by facilitating endosomal trafficking and lysosomal fusion . Tollip was found to be associated with endosomes and recruits target of Myb protein 1 and ubiquitinated proteins .…”

“…Tollip was found to be associated with endosomes and recruits target of Myb protein 1 and ubiquitinated proteins . Tollip‐deficient macrophages exhibit an accumulation of p62 as well as a decrease in endosomal acidity compared to wild‐type cells . The expression of key lysosomal fusion molecules was also compromised in Tollip‐deficient cells and tissues .…”