The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

Abstract

The finding of an effective cure or treatment for neurodegenerative diseases is one of the biggest challenges for this century. Although these diseases show different clinical manifestations, the presence of toxic protein aggregates in the brain of patients is a common feature to all of them, suggesting a loss of protein homeostasis.Aging, the primary risk factor for the majority of neurodegenerative disorders, is linked to the impairment of degradative compartments such as lysosomes and autophagosomes. Besides, many genetic factors for Alzheimer's disease, Parkinson's disease, or frontotemporal dementia, as examples of frequent neurodegenerative diseases, are causative of endo-lysosomal and autophagosomal dysfunctions. There is scientific evidence suggesting that neurons can counteract the accumulation of undegraded cellular material by the secretion of extracellular vesicles (EVs), which are vesicles with a size ranging from 50 to 100 nm generated in a type of endosomal compartment named multivesicular body. EVs play a crucial role in removing cellular waste, promoting protein aggregation, and spreading toxic protein aggregates in the brain of patients. In this review, the interplay between the impairment of degradative compartments, the secretion of EVs, and their pathological/beneficial role in neurodegeneration is described.

Exosomes and GPI-anchored proteins: Judicious pairs for investigating biomarkers from body fluids

“…Involvement in cellular homeostasis Cells secrete exosomes in response to changes in their environmental conditions or to impairment of degradative compartments, thus enabling them to maintain their homeostasis and integrity (reviewed in [16,53,54]). Environmental conditions can drive membrane flux variations, in turn leading to changes in proteins incorporated in exosomal membranes [30].…”

A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

“…Emerging data strongly suggest that the extracellular secretion may also play an important role in the maintenance of intracellular protein homeostasis by cooperating with or even being a part of the PQC system (Desdín-Micó and Mittelbrunn, 2017 ; Xu et al, 2018 ; Guix, 2020 ). In fact, it has been found that several NDs-related proteins are secreted in double membrane spherical particles known as extracellular vesicles.…”

Novel Perspective on Alzheimer’s Disease Treatment: Rosmarinic Acid Molecular Interplay with Copper(II) and Amyloid β

“…Although the causes and the cellular pathways leading to AD pathogenesis are not fully understood, the amyloid cascade hypothesis indicates the accumulation of amyloid β (Aβ) oligomers and fibrils as the main hallmark of AD. Aβ aggregates are very neurotoxic and cause severe damage to neurons; they are responsible for various phenomena, such as oxidation, lipid peroxidation, inflammation, disturbance of cell functions, apoptosis, and neurofibrillary tangles [ 24 , 25 , 26 , 27 , 28 , 29 ]. For these reasons, most AD therapeutic strategies are mainly centered on Aβ targeting, limiting the possibility to exploit new, potential AD treatments based on the implication of diverse mechanisms of AD etiology.…”