Insights Into the Proteomic Profiling of Extracellular Vesicles for the Identification of Early Biomarkers of Neurodegeneration

Abstract

Extracellular vesicles (EVs) are involved in the development and progression of neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Moreover, EVs have the capacity to modify the physiology of neuronal circuits by transferring proteins, RNA, lipids, and metabolites. The proteomic characterization of EVs (exosomes and microvesicles) from preclinical models and patient samples has the potential to reveal new proteins and molecular networks that affect the normal physiology prior to the appearance of traditional biomarkers of neurodegeneration. Noteworthy, many of the genetic risks associated to the development of Alzheimer's and Parkinson's disease affect the crosstalk between mitochondria, endosomes, and lysosomes. Recent research has focused on determining the role of endolysosomal trafficking in the onset of neurodegenerative diseases. Proteomic studies indicate an alteration of biogenesis and molecular content of EVs as a result of endolysosomal and autophagic dysfunction. In this review, we discuss the status of EV proteomic characterization and their usefulness in discovering new biomarkers for the differential diagnosis of neurodegenerative diseases. Despite the challenges related to the failure to follow a standard isolation protocol and their implementation for a clinical setting, the analysis of EV proteomes has revealed the presence of key proteins with post-translational modifications that can be measured in peripheral fluids.

Emerging Roles of Exosomes in Huntington’s Disease

“…Application of omics techniques enabled to map the molecular composition of EV in NDs. While EV protein and miRNA alterations have been studied in more frequent Alzheimer’s and Parkinson’s diseases [ 25 , 134 ], only little is known in HD.…”

Reprogramming Extracellular Vesicles for Protein Therapeutics Delivery

“…EVs are capable of encapsulating various macromolecular cargoes such as proteins, nucleic acids and lipids [ 11 , 12 ]; in addition, various receptors and markers may be present on their surface. Although early works described them as cells’ by-products [ 13 ], a lot of studies report the significant role of EVs as biomarkers for a variety of human pathological conditions nowadays [ 14 , 15 , 16 , 17 , 18 ]. The major advantages of EVs as therapeutic carriers encompass: (i) natural biocompatibility as their envelope is formed from the same cell membrane [ 19 , 20 ], (ii) the ability to pass through the blood–brain barrier [ 21 , 22 ] and (iii) their versatility as a therapeutic tool since surface receptors could be easily modified [ 23 , 24 ].…”

Extracellular Vesicles for the Diagnosis and Treatment of Parkinson’s Disease

“…Additional studies found an increased release of EVs containing α-syn when intracellular protein trafficking through lysosomes was blocked, confirming that lysosomal dysfunction is likely one of the major factors accelerating PD pathology [ 41 - 43 ]. Inhibition of glucocerebrosidase 1 (GBA-1) activity has also increased the release of brain EVs containing α-syn oligomers [ 44 ]. Furthermore, vesicular α-syn is more prone to aggregation than cytosolic α-syn, indicating disease spread in a prion-like fashion from cell to cell.…”