Contribution of Extracellular Vesicles and Molecular Chaperones in Age-Related Neurodegenerative Disorders of the CNS

Abstract

Many neurodegenerative disorders are characterized by the abnormal aggregation of misfolded proteins that form amyloid deposits which possess prion-like behavior such as self-replication, intercellular transmission, and consequent induction of native forms of the same protein in surrounding cells. The distribution of the accumulated proteins and their correlated toxicity seem to be involved in the progression of nervous system degeneration. Molecular chaperones are known to maintain proteostasis, contribute to protein refolding to protect their function, and eliminate fatally misfolded proteins, prohibiting harmful effects. However, chaperone network efficiency declines during aging, prompting the onset and the development of neurological disorders. Extracellular vesicles (EVs) are tiny membranous structures produced by a wide range of cells under physiological and pathological conditions, suggesting their significant role in fundamental processes particularly in cellular communication. They modulate the behavior of nearby and distant cells through their biological cargo. In the pathological context, EVs transport disease-causing entities, including prions, α-syn, and tau, helping to spread damage to non-affected areas and accelerating the progression of neurodegeneration. However, EVs are considered effective for delivering therapeutic factors to the nervous system, since they are capable of crossing the blood–brain barrier (BBB) and are involved in the transportation of a variety of cellular entities. Here, we review the neurodegeneration process caused mainly by the inefficiency of chaperone systems as well as EV performance in neuropathies, their potential as diagnostic biomarkers and a promising EV-based therapeutic approach.

Extracellular Vesicles Slow Down Aβ(1–42) Aggregation by Interfering with the Amyloid Fibril Elongation Step

“…This, in turn, further emphasizes that EV proteins or specific lipids may be important for the inhibitory effect on Aβ(1–42). For example, EVs have been observed to contain chaperones such as Hsp70, which could potentially contribute to the inhibition of Aβ(1–42) aggregation . We report a high degree of similarity in the inhibitory effect of the SH-SY5Y- and HEK-293T-derived EVs, despite their different cellular origins and mean particle size.…”

Gene expression asymmetry in Parkinson’s Disease; variation ofCCTandBEXgene expression levels are correlated with hemisphere specific severity

“…Additionally, the most prominent disease relevant processes based on gene set enrichment were driven by the expression of CCT chaperonin complex subunits (FigA,B; Supplemental Fig1A) The CCT genes express proteins that form the CCT chaperonin complex, which has been reported to be associated with Parkinson's disease (PD) risk as well as being critical in PD processes including alpha-synuclein aggregation [18][19][20]. These genes, as well as other chaperone protein and protein folding related genes, were generally elevated in PD patients compared to healthy controls.…”

Histopathology of Skeletal Muscle in a Distal Motor Neuropathy Associated with a Mutant CCT5 Subunit: Clues for Future Developments to Improve Differential Diagnosis and Personalized Therapy

“…Likewise, mutations in the gene encoding Hsp60 were associated with hypomyelinating defects [31]. We could not find reports on the ability of the CCT complex to fold the myelin proteins, but the interplay of CCT with other molecules involved in myelin formation, such as the members of the Hsp70 family, has been proposed [31,32]. Reports about the expression and function of the CCT complex in human myocardium are not available, but the knock-down of cardiac-CCT subunits in the fly, Drosophila melanogaster, model showed impairment in the structure and function of cardiomyocytes [33].…”