Beyond the synucleinopathies: alpha synuclein as a driving force in neurodegenerative comorbidities

Abstract

The fundamental role that alpha-synuclein (aSyn) plays in the pathogenesis of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, is a well-accepted fact. A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain. Beyond the synucleinopathies, the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer's disease. In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception, the potential role that aSyn may have in these disorders has received relatively little attention. In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities. In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies, we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins, including tau, TDP-43, amyloid-β and prion protein, in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology. We conclude that a growing body of evidence, encompassing neuropathology studies in human brain, animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction, cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities. We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases.

Keywords: Alpha-synuclein; Alzheimer’s disease; Amyloid-β; Comorbidity; Dementia with Lewy bodies; Multiple system atrophy; Neurodegeneration; Parkinson’s disease; Prion protein; Progressive supranuclear palsy; Proteinopathy; TDP-43; Tau.

Fig. 1

The number of articles in Pubmed by year containing the words alpha synuclein and either Parkinson’s disease, Alzheimer’s disease or tau from 1997 to 2018 ((alpha synuclein) AND Parkinson’s disease/Alzheimer’s disease/tau) AND (“1997”[Date - Publication]: “2018”[Date - Publication]) in the title

Fig. 2

Approximate frequency of Lewy pathology reported in other neurodegenerative proteinopathies and in the unimpaired aged population. These estimates do not capture the amount of Lewy pathology present or anatomical distribution of Lewy pathology in relation to the primary pathology, but instead reflect the reporting of the presence of any amount of Lewy pathology in any brain region. Lewy body (LB); multiple system atrophy (MSA); unimpaired aging (Ua), frontotemporal lobe dementia (FTLD), amyotrophic lateral sclerosis (ALS), sporadic Creuzfeldt-Jakob disease (sCJD); Alzheimer’s disease (AD); progressive supranuclear palsy (PSP); corticobasal degeneration (CBD)

Fig. 3

Predicted overlap (yellow) of aSyn in PD (green) with deposition patterns for amyloid-β in Alezheimer’s disease (red) in the brainstem, limbic (e.g. amygdala, hippocampus, anterior cingulate) and subcortical areas (e.g. basal ganglia) and neocortical areas. According to the Thal Phases the deposition of amyloid-β follows a neocortical to limbic/subcortical to brainstem path [102], which is opposite to that seen for aSyn according to the Braak stages of Lewy pathology [97]

Fig. 4

Predicted overlap (yellow) of aSyn in PD (green) with deposition patterns for tau in Alzheimer’s disease and primary age-related tauopathy (red) in the brainstem, limbic (e.g. amygdala, hippocampus, anterior cingulate) and subcortical areas (e.g. basal ganglia) and neocortical areas. According to the Braak stages of neurofibrillary tau pathology [98] the deposition of tau follows a similar involvement of anatomical systems (i.e., brainstem to limbic/subcortical to neocortex) as seen for aSyn for Lewy pathology [97]

Fig. 5

Neuropathological comorbidities associated with the clinical progression of dementia with Lewy bodies (DLB) or progression of premotor Parkinson’s disease (Pm-PD) to Parkinson’s disease (PD) and in a subset of individuals to Parkinson’s disease dementia (PDD). Clinical progression is depicted as increasing darkness of blue. Braak stage of Lewy pathology is depicted in green, frequency ad severity of Alzheimer’s disease (AD) pathology is depicted in yellow and frequency of TAR DNA-binding protein 43 (TDP-43)) pathology in orange