Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.

Toshiki Uchihara,Benoit I Giasson

doi:10.1007/s00401-015-1485-1

Toshiki Uchihara, Benoit I Giasson

Open Access

https://doi.org/10.1007/s00401-015-1485-1

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Abstract

Progressive aggregation of alpha-synuclein (αS) through formation of amorphous pale bodies to mature Lewy bodies or in neuronal processes as Lewy neurites may be the consequence of conformational protein changes and accumulations, which structurally represents “molecular template”. Focal initiation and subsequent spread along anatomically connected structures embody “structural template”. To investigate the hypothesis that both processes might be closely associated and involved in the progression of αS pathology, which can be observed in human brains, αS amyloidogenic precursors termed “seeds” were experimentally injected into the brain or peripheral nervous system of animals. Although these studies showed that αS amyloidogenic seeds can induce αS pathology, which can spread in the nervous system, the findings are still not unequivocal in demonstrating predominant transsynaptic or intraneuronal spreads either in anterograde or retrograde directions. Interpretation of some of these studies is further complicated by other concurrent aberrant processes including neuroimmune activation, injury responses and/or general perturbation of proteostasis. In human brain, αS deposition and neuronal degeneration are accentuated in distal axon/synapse. Hyperbranching of axons is an anatomical commonality of Lewy-prone systems, providing a structural basis for abundance in distal axons and synaptic terminals. This neuroanatomical feature also can contribute to such distal accentuation of vulnerability in neuronal demise and the formation of αS inclusion pathology. Although retrograde progression of αS aggregation in hyperbranching axons may be a consistent feature of Lewy pathology, the regional distribution and gradient of Lewy pathology are not necessarily compatible with a predictable pattern such as upward progression from lower brainstem to cerebral cortex. Furthermore, “focal Lewy body disease” with the specific isolated involvement of autonomic, olfactory or cardiac systems suggests that spread of αS pathology is not always consistent. In many instances, the regional variability of Lewy pathology in human brain cannot be explained by a unified hypothesis such as transsynaptic spread. Thus, the distribution of Lewy pathology in human brain may be better explained by variable combinations of independent focal Lewy pathology to generate “multifocal Lewy body disease” that could be coupled with selective but variable neuroanatomical spread of αS pathology. More flexible models are warranted to take into account the relative propensity to develop Lewy pathology in different Lewy-prone systems, even without interconnections, compatible with the expanding clinicopathological spectra of Lewy-related disorders. These revised models are useful to better understand the mechanisms underlying the variable progression of Lewy body diseases so that diagnostic and therapeutic strategies are improved.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1485-1) contains supplementary material, which is available to authorized users.

Highlights

Eosinophilic inclusions with halo, known as Lewy bodies, (LBs) were identified by Friedrich Heinrich Lewy in the dorsal motor nucleus of vagus and substantia innominata in the brains of patients with Parkinson disease (PD) [43, 69]
Detailed analyses of the initial presentation of αS inclusions throughout the neuroaxis in these mice, before they are symptomatic, showed that they randomly appear without any clustering or direct evident of general spread [54]. This finding is more consistent with concurrent multifocal formation of αS inclusions with variable spreads as we suggest could explain some of the presentation of Lewy pathology in human brains
A subset of these mice still developed motor impairment with central nervous system (CNS) αS pathology identical to mice without nerve transection. These findings demonstrated that retrograde transport of PFSPs is partially responsible for the induction of CNS αS pathology in this model, but either other routes including perhaps other minor nerves or transport through blood may be involved in inducing distant CNS αS pathology in predefined fashion

Summary

Introduction

Eosinophilic inclusions with halo, known as Lewy bodies, (LBs) were identified by Friedrich Heinrich Lewy in the dorsal motor nucleus of vagus (dmX) and substantia innominata in the brains of patients with Parkinson disease (PD) [43, 69]. A more direct experimental paradigm to try to demonstrate the involvement of αS conformational templating in the induction and spread of αS is the brain injection of in vitro produced recombinant PFSPs. The cerebral injection of recombinant, exogenous PFSPs can induce the formation of intracellular αS inclusion pathology in M83+/+ αS mice resulting in the typical motor impairments and paralysis characteristic of the phenotype that occurs in these mice with aging [13, 125, 162].

Results

Conclusion