Intrastriatal Administration of Exosome-Associated Pathological Alpha-Synuclein Is Not Sufficient by Itself to Cause Pathology Transmission

Abstract

α-Synuclein (α-syn) has been genetically and biochemically linked to the pathogenesis of Parkinson's disease (PD). There is accumulating evidence that misfolded α-syn species spread between cells in a prion-like manner and seed the aggregation of endogenous protein in the recipient cells. Exosomes have been proposed to mediate the transfer of misfolded α-syn and thus facilitate disease transmission, although the pathological mechanism remains elusive. Here, we investigated the seeding capacity of exosomeassociated α-syn, in vivo. Disease-associated α-syn was present in exosome fractions isolated from transgenic A53T mouse brain. However, following intrastriatal injection of such exosomes in wild-type (wt) mice, we were not able to detect any accumulation of endogenous α-syn. In addition, recombinant fibrillar α-syn, when loaded to isolated brain exosomes, induced minor pathological α-syn brain accumulation at 7 months post injection. These data suggest that exosomes neutralize the effect of toxic α-syn species and raise additional questions on their paracrine modulatory role in disease transmission.

Blood-Derived α-Synuclein Aggregated in the Substantia Nigra of Parabiotic Mice

“…It has been reported that the aggregation propensities of mutant α-synuclein and the neurotoxicity of oligomers are related to the pathogenesis of PD [ 2 , 21 ]. Misfolded α-synuclein can be transmitted in exosomes; however, discrepancies in pathological results among different studies, due to the concentrations of exosomes injected, caused concern [ 22 , 23 ]. Monomeric α-synuclein disrupted the BBB by interacting with pericytes in patients with PD [ 24 ].…”

Neurons and Glia Interplay in α-Synucleinopathies

“…Another mechanism for intercellular communication is via exosomes. Although extensive work has been done regarding the role of exosomes in neuronal aSyn transmission and disease pathology [ 366 , 579 , 580 , 581 , 582 ], few studies have proposed a vesicular-mediated transfer of neuroprotective molecules from astrocytes to neurons [ 583 , 584 ] or an exosome-related aSyn spread from neurons to astrocytes [ 585 , 586 ].…”

Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

“…The addition of EVs isolated from WT mouse brain induces the assembly of recombinant α-syn preformed fibrils (PFFs) into higher-order multimers in vitro. In the same timeframe, no multimerization of α-syn PFF in the absence of EVs was observed [ 97 ]. However, similarly to what was described for Aβ [ 47 ], the pre-incubation of α-syn PFFs with these EVs neutralized the detrimental effects of α-syn PFFs in vitro (i.e., reduced uptake by primary cortical cultures) and in vivo (i.e., inability to induce α-syn accumulation after intrastriatal injection in WT mice) [ 97 ].…”

“…In the same timeframe, no multimerization of α-syn PFF in the absence of EVs was observed [ 97 ]. However, similarly to what was described for Aβ [ 47 ], the pre-incubation of α-syn PFFs with these EVs neutralized the detrimental effects of α-syn PFFs in vitro (i.e., reduced uptake by primary cortical cultures) and in vivo (i.e., inability to induce α-syn accumulation after intrastriatal injection in WT mice) [ 97 ]. Interestingly, the A53T α-syn mutant displays an increased association with EVs, leading to the speculation that pathogenic α-syn species may be preferentially sorted into EVs [ 90 ].…”

“…Furthermore, α-syn-containing EVs derived from serum of PD patients trigger α-syn aggregation, dopaminergic degeneration and motor deficits when administered into the striatum of WT mice [ 104 ]. However, EVs isolated from A53T α-syn transgenic mouse brain were unable to induce α-syn pathology and motor deficits after their intrastriatal injection in WT mice [ 97 ].…”