Lack of pathogenic potential of peripheral α-synuclein aggregates from Parkinson’s disease patients

Abstract

In Parkinson’s disease (PD) there is widespread accumulation in the brain of abnormal α-synuclein aggregates forming intraneuronal Lewy bodies (LB). It is now well established that LB-type α-synuclein aggregates also occur in the peripheral autonomic nervous system in PD, from where it has been speculated they may progressively spread to the central nervous system through synaptically-connected brain networks and reach the substantia nigra to trigger herein dopaminergic dysfunction/degeneration and subsequent parkinsonism. Supporting a pathogenic role for α-synuclein aggregates we have previously shown that LB purified from postmortem PD brains promote α-synuclein pathology and dopaminergic neurodegeneration when intracerebrally inoculated into wild-type mice. However, the pathogenic capacity of PD-derived peripheral α-synuclein aggregates remains unknown. Here we addressed this question using purified LB-type α-synuclein aggregates from postmortem PD stellate ganglia (SG), a paravertebral sympathetic ganglion that exhibits consistent and conspicuous Lewy pathology in all PD patients. In contrast to our previous findings using nigral LB extracts, intracerebral inoculation of SG-derived LB into mice did not trigger long-term nigrostriatal neurodegeneration nor α-synuclein pathology. The differential pathogenic capacities of central- and peripheral-derived α-synuclein aggregates appear independent of the absolute amount and basic biochemical properties of α-synuclein within these aggregates and may rely instead on differences in α-synuclein conformation and/or yet unrecognized brain region-specific intrinsic factors. Our results argue against a putative pathogenic capacity of peripheral α-synuclein aggregates to promote α-synuclein pathology in the brain, propagate between neuronal networks or induce neurodegeneration.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0509-1) contains supplementary material, which is available to authorized users.

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

“…Moreover, phosphorylation of α‐synuclein, which is widely considered to be an index of PD pathology, (1) can also be seen in tissue from control subjects; (2) may result from a nonspecific cross‐reaction with other phospho‐proteins, such as phosphorylated neurofilaments; and (3) does not affect neuronal survival in in vitro PD models . In addition, peripheral α‐synuclein aggregates from PD patients, which are believed to spread to the brain and initiate PD, lack the capacity to promote α‐synuclein pathology, propagate between neuronal networks, or induce neurodegeneration when inoculated into experimental animals . Finally, in the original studies reporting an apparent transmission of LB pathology from host PD patients to embryonic mesencephalic neurons grafted into the striatum many years earlier, which gave rise to the currently prevalent pathogenic hypothesis of cell‐to‐cell transmission of α‐synuclein, LB formation occurred exclusively within grafted neurons that contained adult levels of neuromelanin and was not observed in nonmelanized grafted cells or intrinsic striatal neurons of the host.…”

“…78 In addition, peripheral α-synuclein aggregates from PD patients, which are believed to spread to the brain and initiate PD, lack the capacity to promote α-synuclein pathology, propagate between neuronal networks, or induce neurodegeneration when inoculated into experimental animals. 79 Finally, in the original studies reporting an apparent transmission of LB pathology from host PD patients to embryonic mesencephalic neurons grafted into the striatum many years earlier, 80,81 which gave rise to the currently prevalent pathogenic hypothesis of cell-to-cell transmission of α-synuclein, LB formation occurred exclusively within grafted neurons that contained adult levels of neuromelanin and was not observed in nonmelanized grafted cells or intrinsic striatal neurons of the host. Therefore, the latter studies may not in fact reflect a host-to-graft propagation of α-synuclein as was widely interpreted but, rather, indicate that grafted cells had reached pathogenic levels of intracellular neuromelanin accumulation.…”

What Is the Evidence that Parkinson’s Disease Is a Prion Disorder, Which Originates in the Gut?

“…As Tysnes and colleagues [ 128 ] included only 4050 patients with full truncal vagotomy, in contrast to 5339 patients from the study by Svensson et al [ 28 ], any significant difference for the risk of PD between the vagotomy group and reference matched populations has been shown [ 128 ]. Supporting this, recently, Recasens et al [ 129 ] have argued against a pathogenic ability of peripheral α-synuclein assemblies in promoting α-synuclein pathology in the brain. In their study intracerebral inoculation of mice with α-synuclein aggregates from postmortem PD stellate ganglia (paravertebral sympathetic ganglion) triggered neither nigrostriatal neurodegeneration nor α-synuclein pathology in the SNpc [ 129 ].…”

“…Supporting this, recently, Recasens et al [ 129 ] have argued against a pathogenic ability of peripheral α-synuclein assemblies in promoting α-synuclein pathology in the brain. In their study intracerebral inoculation of mice with α-synuclein aggregates from postmortem PD stellate ganglia (paravertebral sympathetic ganglion) triggered neither nigrostriatal neurodegeneration nor α-synuclein pathology in the SNpc [ 129 ]. However, contrary to these findings in their previous report nigral LB extracts from PD patients administered intracerebrally to animals induced α-synuclein pathology, neuroinflammation and finally neurodegeneration in the SNpc [ 120 ].…”

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“…The role of peripheral α-synuclein spread, however, is less well understood. In a recent study published in Acta Neuropathologica Communications, [3] researchers evaluated the pathogenic potential of peripheral α-synuclein aggregates by injecting LB extracts of human PD patients into the SNpc of wild-type mice. The unique aspect of this study was the fact that the researchers used LB obtained from the stellate ganglia, a peripheral paravertebral sympathetic ganglion that consistently exhibits LB pathology in patients with PD.…”