Cogs in the autophagic machine—equipped to combat dementia-prone neurodegenerative diseases

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Rensu Theart¹  Ben Loos²  Sholto de Wet² 

[1] Department of Electric and Electronic Engineering, Stellenbosch University, Stellenbosch, South Africa;Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa;

关键词: autophagy;    mitochondrial function;    lysosomes;    mitophagy;    neurodegenerative diseases;    proteostasis;   

DOI  :  10.3389/fnmol.2023.1225227

 received in 2023-05-18, accepted in 2023-07-31,  发布年份 2023

来源: Frontiers

【 摘 要 】

Neurodegenerative diseases are often characterized by hydrophobic inclusion bodies, and it may be the case that the aggregate-prone proteins that comprise these inclusion bodies are in fact the cause of neurotoxicity. Indeed, the appearance of protein aggregates leads to a proteostatic imbalance that causes various interruptions in physiological cellular processes, including lysosomal and mitochondrial dysfunction, as well as break down in calcium homeostasis. Oftentimes the approach to counteract proteotoxicity is taken to merely upregulate autophagy, measured by an increase in autophagosomes, without a deeper assessment of contributors toward effective turnover through autophagy. There are various ways in which autophagy is regulated ranging from the mammalian target of rapamycin (mTOR) to acetylation status of proteins. Healthy mitochondria and the intracellular energetic charge they preserve are key for the acidification status of lysosomes and thus ensuring effective clearance of components through the autophagy pathway. Both mitochondria and lysosomes have been shown to bear functional protein complexes that aid in the regulation of autophagy. Indeed, it may be the case that minimizing the proteins associated with the respective neurodegenerative pathology may be of greater importance than addressing molecularly their resulting inclusion bodies. It is in this context that this review will dissect the autophagy signaling pathway, its control and the manner in which it is molecularly and functionally connected with the mitochondrial and lysosomal system, as well as provide a summary of the role of autophagy dysfunction in driving neurodegenerative disease as a means to better position the potential of rapamycin-mediated bioactivities to control autophagy favorably.

【 授权许可】

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Copyright © 2023 de Wet, Theart and Loos.