Abstract
Alpha-synuclein aggregation plays a central role in Parkinson's disease pathology. Direct transmission of alpha-synuclein from pathologically affected to healthy unaffected neurons may be important in the anatomical spread of the disease through the nervous system. We have demonstrated that exosomes released from alpha-synuclein over-expressing SH-SY5Y cells contained alpha-synuclein and these exosomes were capable of efficiently transferring alpha-synuclein protein to normal SH-SY5Y cells. Moreover, the incubation of cells with ammonium chloride or bafilomycin A1 to produce the lysosomal dysfunction recently reported in Parkinson's disease led to an increase in the release of alpha-synuclein in exosomes and a concomitant increase in alpha-synuclein transmission to recipient cells. This study clearly demonstrates the importance of exosomes in both the release of alpha synuclein and its transmission between cells and suggests that factors associated with PD pathology accelerate this process. These mechanisms may play an important role in PD pathology and provide a suitable target for therapeutic intervention.
Highlights
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised pathologically by the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LB) which are intra-cytoplasmic inclusions containing high levels of alpha-synuclein (Spillantini et al, 1997)
Exosomes released by SH-SY5Y cells contained and transferred alpha-synuclein
Quantitation of alpha-synuclein levels in conditioned medium and flow through using ELISA analysis (Fig. 1e) confirmed the majority of the alpha-synuclein was associated with the exosomes
Summary
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised pathologically by the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LB) which are intra-cytoplasmic inclusions containing high levels of alpha-synuclein (Spillantini et al, 1997). The discovery of mutations (A53T, A30P, E46K) and multiplications of the alphasynuclein gene in familial forms of PD further demonstrate the importance of alpha-synuclein to PD pathology (Lee and Trojanowski 2006). Host-to-graft propagation of alpha-synuclein-positive Lewylike pathology has recently been demonstrated in long-term mesencephalic transplants in PD patients (Li et al, 2008; Kordower et al 2008). In vitro experiments co-culturing over-expressing cells with non-expressing and neuronal precursor cells showed cell-to-cell transmission of alpha-synuclein (Desplats et al, 2009). These studies support the notion that alpha-synuclein can be directly transmitted from pathologically affected to healthy unaffected neurons leading to.
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