Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?

Abstract

Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.

Keywords: Alzheimer’s disease; exosomal shuttle RNA; exosomes; neurodegenerative diseases; prions.

Figure 1

Exosome biogenesis occurs within MVBs of the endosomal system. Following endocytosis into early endosomes (EE), the cargo is packaged into ILVs within MVBs upon inward budding of the membrane. Four different mechanisms have been described to facilitate this process: mono-ubiquitination and the ESCRT machinery; association with lipid rafts; higher-ordered oligomerization; and segregation into microdomains by ceramide. MVBs can then fuse with lysosomes resulting in degradation of the cargo, or alternatively, the MVBs can fuse with the plasma membrane, resulting in release of the ILVs as exosomes, a process which is regulated by Rab GTPases.

Figure 2

Exosomes are small membrane bound vesicles sharing similar topology to the plasma membrane. They contain mRNA and miRNA, and a vast array of different proteins depending on their host cell. However they are generally all enriched in proteins involved in MVB formation, tetraspanins, membrane transport and fusion and a number of cytosolic proteins. In addition to these generic proteins, proteins associated with neurodegenerative diseases such as Alzheimer’s, Prion disease, and Parkinson’s disease have been identified in exosomes.