Abstract
Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport. We observed that the three fibrils were transported in both anterograde and retrograde directions but with strikingly different efficiencies. The amount of Aβ42 fibrils transported was ten times higher than that of the other two fibrils. HTTExon1 was efficiently transported in the retrograde direction but only marginally in the anterograde direction. Finally, using neurons from two distinct mutant mouse strains whose axons are highly resistant to neurodegeneration (WldS and Sarm1−/−), we found that the three different fibrils were secreted by axons after anterograde transport, in the absence of axonal lysis, indicating that trans-neuronal spread can occur in intact healthy neurons. In summary, fibrils of α-synuclein, Aβ42 and HTTExon1 are all transported in axons but in directions and amounts that are specific of each fibril. After anterograde transport, the three fibrils were secreted in the medium in the absence of axon lysis. Continuous secretion could play an important role in the spread of pathology between neurons but may be amenable to pharmacological intervention.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1538-0) contains supplementary material, which is available to authorized users.
Highlights
It is generally accepted that the prion-like behavior of some aggregation prone proteins is associated with the spread of pathology observed in several neurodegenerative diseases
For Parkinson disease (PD), early evidence came from the startling observation that Lewy bodies, which are in part comprised of α-synuclein (α-syn) fibrils, were present in fetal nigral neurons which had been grafted into the brain of PD patients several years before as a therapeutic measure [24, 26]
Together these results form the basis for a model in which the prion-like properties of α-syn fibrils and their axonal transport might be responsible for the progression of PD pathology
Summary
It is generally accepted that the prion-like behavior of some aggregation prone proteins is associated with the spread of pathology observed in several neurodegenerative diseases. For Parkinson disease (PD), early evidence came from the startling observation that Lewy bodies, which are in part comprised of α-synuclein (α-syn) fibrils, were present in fetal nigral neurons which had been grafted into the brain of PD patients several years before as a therapeutic measure [24, 26]. This surprising finding suggested that α-syn aggregates may propagate from the host diseased tissue into the graft tissue [10]. MHTT fibrils can spread between neurons in various in vitro culture systems [35, 40]
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