Abstract
Most common neurodegenerative diseases (NDs) are characterized by deposition of protein aggregates that are resulted from misfolding, dysregulated trafficking, and compromised proteolytic degradation. These proteins exert cellular toxicity to a broad range of brain cells and are found in both neurons and glia. Extracellular monomeric and oligomeric ND-associated proteins are taken up by astrocytes, the most abundant glial cell in the brain. Internalization, intracellular trafficking, processing, and disposal of these proteins are executed by the endosomal-lysosomal system of astrocytes. Endosomal-lysosomal organelles thus mediate the cellular impact and metabolic fate of these toxic protein species. Given the indispensable role of astrocytes in brain metabolic homeostasis, the endosomal-lysosomal processing of these proteins plays a fundamental role in altering the trajectory of neurodegeneration. This review aims at summarizing the mounting evidence that has established the essential role of astrocytic endosomal-lysosomal organelles in the processing of amyloid precursor proteins, Apolipoprotein E (ApoE), tau, alpha synuclein, and huntingtin, which are associated with NDs such as Alzheimer’s, Parkinson’s, and Huntington diseases.
Highlights
By virtue of the metabolic roles of endolysosomes, cell metabolism and energetics can be compromised, failing the neuro-supportive function offered by astrocytes
Defining the mechanism of how astrocytes are activated by endolysosomal processing of neurodegenerative diseases (NDs) proteins will help elucidate the role of inflammatory response in NDs
It appears that promoting autophagic protein degradation and lysosome biogenesis facilitate astrocytic clearance of the ND proteins
Summary
Storage and processing of energy precursor molecules require additional repertoire of organellar functions. To compartmentalize these metabolic functions within the brain, the tasks are delegated to the supporting cell astrocytes. Astrocytes are responsible for storing glycogen and lipids and possess the organellar machinery to process them into energy precursor molecules [6]. Mounting evidence has revealed the roles of these reactive astrocytes in aging and neurodegeneration (ND) [8,9] In addition to their secretory role, astrocytes are essential for clearance and processing of proteins from the extracellular space. Astrocytic regulation of the metabolic fate of these ND-associated proteins is a major factor contributing to the disease pathogenesis and progression
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