Propagation of alphasynuclein pathology hypothes

Authors: Toshiki Uchihara Benoit I Giasson

Publish Date: 2015/10/07

Volume: 131, Issue: 1, Pages: 49-73

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Abstract

Progressive aggregation of alphasynuclein 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 Lewyprone 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 Lewyprone systems even without interconnections compatible with the expanding clinicopathological spectra of Lewyrelated 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 improvedEosinophilic inclusions with halo now 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 Initially their presence in the substantia nigra SN was not readily recognized probably because they were less frequent in SN and their relevance to PD had not been established until Konstantin Nikolaevich Tretiakoff identified a consistent association between nigral degeneration with LBs as a pathological substrate for PD 73 114 However it remained unexplained how these inclusions at multiple brain regions were related to characteristic motor deficits of PD until dopaminergic deficit of nigrostriatal system was identified as a major mechanism of PD 85 164 largely involved in the motor presentation of PD This nigracentered explanation was reinforced after dramatic improvement by replacement therapy with levodopa 6 39Histochemical identification of Lewy pathology was improved by silver impregnations 175 and later by ubiquitin or neurofilament immunohistochemistry IHC 71 Ultimately IHC for alphasynuclein αS which is its major molecular component 168 is the most sensitive and specific gold standard to detect various types of Lewy pathologies Amorphous early αS deposits in the neuronal cytoplasm known as pale body and pale neurites 92 suggests that initial amorphous αS deposits may evolve progressively into more aggregated typical LBsIn addition to this progressive aggregation of αS in the neuronal cytoplasm and neurites the identification of LBs in the cerebral cortices in patients with atypical dementia 102 103 141 and in peripheral tissues 180 raised attention for their more extensive distribution that might explain other related clinical manifestations Even after the identification of αS as a major component of LBs however it remains to be clarified how when and where LBs are formed 22 45 Because Lewy pathology is more abundant in the lower brainstem in a majority of cases it is generally assumed as if Lewy pathology is initiated in the lower brainstem and spreads into upper brainstem 21 45 This idea led to a hypothesis that conformational change of αS to form aggregates might have templated itself to spread along neuroanatomical connections which may be similar to prion disease at least partly Because this unified hypothesis is highly convenient and attractive to explain both local molecular change of αS as “a molecular template” and its stereotyped spread as “a structural template” this combination is now enjoying the initial honeymoon of a happy marriage when everything is usually considered in favor of this hypothesis To make this marriage profoundly fruitful or at least acceptably fruitful even after the honeymoon period some skepticism may be useful to recognize its potential pitfalls possible misunderstandings or misinterpretations if anyIn this review we will first discuss the molecular basis for some of the animal experimental studies that may support a conformational templating of αS protein as a pivotal mechanism involved in neuroanatomical spread of αS pathology However we also consider how this simplistic mechanistic view does NOT fully take into account the global complexities of induced experimental paradigms and the variable presentations of human neuropathology We explore the additional biological changes and unique neuroanatomical properties associated with Lewy pathology that might provide alternative explanations for its distribution and clinical presentations Indeed specific neuroanatomical and morphological properties of select neuronal populations combined with alterations in multiple synergistic pathogenic mechanisms likely explain the variable clinical presentation of neurodegenerative diseases associated with Lewy pathology αS pathology can often present with concomitant cerebral Amyloid βprotein Aβ tau and/or TAR DNAbinding protein43 TDP43 inclusion pathology which could influence both the formation of αS pathology and the clinical findings in some patients 86 104 but these topics are beyond the scope of this reviewSchematic representation of the molecular changes resulting in αS pathological inclusions a αS is naturally predominantly an unstructured soluble protein green shapes that can randomly convert to acquire a βpleated sheet conformation red shapes Once in this conformation αS can polymerize into longer amyloid precursor units and eventually fibrils shown as negative stained αS fibrils assembled in vitro and observed by electron microscopy bar 100 nm that coalesce to form pathological inclusions shown as Lewy bodies LBs staining with an antiαS antibody bar 25 μm b αS can potentially polymerize into amyloid precursor units and amyloidogenic fibrils that at the molecular level have subtle conformational differences red shapes versus blue shapes and these are not compatible for copolymerizing resulting in a “strain”like specific polymersThe in vitro polymerization of soluble αS into amyloid fibrils is characterized by a lag phase followed by a rapid increase in fibril formation that can be promoted by increasing αS protein concentration 118 138 177 191 Therefore it appears that the formation of a critical amount of αS amyloid precursors that may stochastically form in solution and is favored by increased protein concentration which may also stabilize these structures due to increased protein interactions is an important limiting step in driving αS amyloid formation Experimentally the simple addition of preformed fibrillar αS precursors PFSPs also termed “seeding” or “nucleation” to overcome this threshold can rapidly promote the recruitment of unstructured αS molecules into amyloidogenic permissive structure resulting into a synergistic formation of amyloid fibrils Fig 1 191 This in vitro process of using PFSPs to convert normal αS into amyloid precipitating the formation of mature pathological inclusions has been termed “conformational templating” and provides an interesting model that could explain at least in part the spread of αS pathology that tracks with progression of neurodegenerative process in human brains

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