Research Topic

Reports on Cellular Homeostasis in the Brain: Protein and Lipid Metabolism and Consequences in Aging and Neurodegeneration

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Brain homeostasis is critical for function and there is increasing evidence that disrupted catabolism by the major pathways responsible for turnover of cellular constituents can be deleterious to human health. The major pathway for the turnover of proteins are the ubiquitin-proteasome system (UPS), ...

Brain homeostasis is critical for function and there is increasing evidence that disrupted catabolism by the major pathways responsible for turnover of cellular constituents can be deleterious to human health. The major pathway for the turnover of proteins are the ubiquitin-proteasome system (UPS), macroautophagy (or autophagy), chaperone mediated autophagy (UPS), the latter two involving lysosomal degradation. Moreover, macroautophagy is also responsible for the degradation of dysfunctional or redundant vesicles and organelles, while both macroautophagy and lysosomes metabolize lipids.

Ultimately, the role of these catabolic systems is to reduce the presence of proteotoxic and lipotoxic materials to recycling redundant cellular constituents. In humans, we have multiple lines of evidence that when these systems are reduced or fail, catastrophic events can occur. Canonical research on lysosomal storage disorders illustrates the devastating neurological events that occur when genetic mutations result in loss of lysosomal function. Diseases like Neimann-Pick’s and Gaucher’s disease can result in the toxic elevation of lipids and disease progression. Both these diseases also have pathological parallels to Alzheimer’s and Parkinson’s disease, demonstrating common pathways for neurodegeneration.

Moreover, it is recognized that with aging, there is a decline in the protein turnover pathways, and insufficient protein clearance may be critical to all neurodegenerative diseases of the aging as they share a common pathological characterization – presence of proteinopathy, or more specifically aggregopathy. One example is the loss of UPS activity increasing the poly-ubiqutinated and misfolded proteins. Under stress conditions (including the presence of aggregated proteins or dysfunctional mitochondria), autophagy can be induced, offering a therapeutic opportunity to enhance its function, an important research focus as all clearance mechanisms can be utilized to correct destabilized cellular activity.

This Research Topic will focus on the major cellular pathways involved in protein, lipid, and organellar turnover, as well the cellular outcome of failed or reduced turnover in aging and neurodegeneration. Opportunities to enhance UPS, CMA or autophagic activity will also be explored as translational strategies are important in addressing failed cellular catabolism and abate the impact these diseases have on human health.


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