Abstract
The intercellular transfer of misfolded proteins has received increasing attention in various neurodegenerative diseases characterized by the aggregation of specific proteins, as observed in Alzheimer’s, Parkinson’s and Huntington’s disease. One hypothesis holds that intercellular dissemination of these aggregates within the central nervous system results in the seeded assembly of the cognate soluble protein in target cells, similar to that proposed for transmissible prion diseases. The molecular mechanisms underlying the intercellular transfer of these proteinaceous aggregates are poorly understood. Various transfer modes of misfolded proteins including continuous cell-cell contacts such as nanotubes, unconventional secretion or microvesicle/exosome-associated dissemination have been suggested. Cells can release proteins, lipids and nucleic acids by vesicular exocytosis pathways destined for horizontal transfer. Encapsulation into microvesicular/exosomal vehicles not only protects these molecules from degradation and dilution in the extracellular space but also facilitates delivery over large distances, e.g. within the blood flow or interstitial fluid. Specific surface ligands might allow the highly efficient and targeted uptake of these vesicles by recipient cells. In this review, we focus on the cell biology and function of neuronal microvesicles/exosomes and discuss the evidence for pathogenic intercellular protein transfer mediated by vesicular carriers.
Highlights
The intercellular transfer of misfolded proteins has received increasing attention in various neurodegenerative diseases characterized by the aggregation of specific proteins, as observed in Alzheimer’s, Parkinson’s and Huntington’s disease
We focus on the cell biology and function of neuronal microvesicles/exosomes and discuss the evidence for pathogenic intercellular protein transfer mediated by vesicular carriers
The transneuronal spreading of oligomers or fibrillar aggregates is increasingly recognized in a variety of neurodegenerative disorders including tau protein and amyloid-β peptide in Alzheimer’s disease, superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis (ALS), huntingtin in Huntington’s disease (HD) and α-synuclein in Parkinson’s disease (PD)
Summary
Microparticles have been isolated from various body fluids such as urine, ascites, saliva, breast milk and blood by ultracentrifugation, ultrafiltration or immunoprecipitation (Simpson et al 2009). In addition to a mere storage function, the MVE can either fuse with the lysosome, followed by the degradation of ILVs, or with the plasma membrane to release the ILVs as exosomes into the extracellular space. Whether these different pathways correspond to distinct subclasses of MVEs or whether each MVE can switch between the different itineries described above is unknown. On transmission of electron or cryo-electron microscopic images, exosomes appear as vesicles of 40–100 nm in diameter with a characteristic round or cup-shaped morphology (Thery et al 2006; Conde-Vancells et al 2010) Exosomes differ in their origin and in their protein and lipid composition. Proteins derived from the nucleus, mitochondria or endoplasmic reticulum are mainly excluded from the exosomal pathway
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