A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson's Disease

Abstract

Extracellular vesicles including exosomes are released by a variety of cell types including neurons and exhibit molecular profiles that reflect normal and disease states. As their content represents a snapshot of the intracellular milieu, they could be exploited as biomarkers of the otherwise inaccessible brain microenvironment. In addition they may contribute to the progression of neurodegenerative disorders by facilitating the spread of misfolded proteins at distant sites or activating immune cells. This review summarizes recent advances in the study of exosomes in Parkinson's disease pathophysiology and their potential as disease biomarkers.

Keywords: Aggregation; LRRK2; alpha-synuclein; biomarker; exosome; neurodegeneration.

Fig.1

Exosome signaling in Parkinson’s disease pathobiology. Exosomes are generated within the multivesicular bodies (MVB) of the endosomal-lysosomal pathway. Genes that are implicated in familial forms of PD such as VPS35, LRRK2, ATP13A2 and Parkin, function in this pathway as shown in the diagram. Heterozygous mutations in GBA that increase the risk of PD by 6-fold impair lysosomal function. LRRK2 regulates this pathway at multiple steps through its kinase activity and is also an exosomal cargo protein (shown in green). α-Synuclein (red) misfolding is considered a key pathogenic event in sporadic PD. α-Synuclein is trafficked via the endosomal pathway by NEDD4/USP8 regulated ubiquitination (Ub) or sumoylation (SUMO) and released in exosomes. Exosomal α-synuclein, LRRK2 or other proteins may contribute to PD pathology by modulating microglial cell activation, facilitating the propagation of proteopathic α-synuclein assemblies or additional signaling events.