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

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 i...

Robust Central Nervous System Pathology in Transgenic Mice following Peripheral Injection of α-Synuclein Fibrils

“…However, the possibility that in vivo, a small amount of exogenous Δ71-82 ␣S might spontaneously acquire amyloidogenic properties over time cannot be excluded, since under nonphysiological conditions (i.e., the presence of SDS), it can be artificially induced to form amyloid fibrils (51). A more parsimonious explanation for the findings that soluble forms of ␣S can also induce ␣S pathology is that additional nonexclusive mechanisms, perhaps including immune activation, can contribute to inducing and/or promoting ␣S inclusion pathology formation (6,52,53).…”

“…␣S pathological inclusions, which are also termed Lewy bodies or Lewy neurites, predominantly occur in neurons and are a defining feature of Parkinson's disease (PD) (1)(2)(3)(4)(5)(6)(7), but in other diseases such as multiple system atrophy, they can predominantly occur in oligodendrocytes (6,(8)(9)(10). A direct role for ␣S in neurodegeneration was established by the discovery of several genetic alterations in the ␣S gene (SNCA), in the form of missense mutations or increased copy number, which result in autosomal-dominant PD or the related disease, dementia with Lewy bodies (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

Propagation of Aβ, tau and α-synuclein pathology between experimental models and human reality: prions, propagons and propaganda

“…Experimental studies using α-synuclein transgenic mice, but in some cases even using wild type mice, have demonstrated that brain inoculations with pre-aggregated α-synuclein "seeds", capable of initiating protein templating of endogenous α-synuclein to form aggregates, can result in neuronal spread of α-synuclein inclusion pathology in either retrograde or anterograde direction and even sometimes transsynaptic spread [7]. This is in contrast with a predominantly retrograde intraneuronal spread of α-synuclein pathology in human brain, which occurs preferentially in neurons with hyperbranching axons, suggesting that it is probably not only molecular propensities of α-synuclein itself but also underlying neuroanatomical structure that influences templating of α-synuclein-related neurodegeneration.…”

“…To explain the variable distribution of α-synuclein lesions in the human nervous system, a novel concept of "multifocal Lewy body disease" (emphasized here in the α-synuclein review) is proposed [7]. Independent and parallel appearance of focal Lewy body pathology in multiple neuronal groups, regardless of their transsynaptic connections, may better explain the variable clinicopathological pictures, more extensively recognized recently in a clinical setting.…”

Myricetin Isolated From Turbinaria Ornata Ameliorates Rotenone Induced Parkinsonism in Drosophila Melanogaster

“…An important hallmark of PD is Lewy's body inclusions, which are formed in dopaminergic cell aggregation area like substantia nigra (SN), dorsal nucleus of the vagus nerve and leads to the degeneration of DA neurons. Decrease in dopamine level forms the imbalance between dopaminergic and acetylcholine system which develops a series of PD symptoms [4,5]. Targeting phytochemicals and bioactive compounds from nature are significant in treating neurodegenerative diseases.…”