Unique \u03b1-synuclein pathology within the amygdala in Lewy body dementia: implications for disease initiation and progression

Zachary A Sorrentino,Niran Vijayaraghavan,Jess-Karan S Dhillon,Marshall S Goodwin,Cara J Riffe,Anthony T Yachnis,Kimberly-Marie Gorion,Benoit I Giasson,Lawrence I Golbe,Yuxing Xia,Karen N Mcfarland

doi:10.1186/s40478-019-0787-2

Zachary A Sorrentino, Niran Vijayaraghavan + Show 9 more

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https://doi.org/10.1186/s40478-019-0787-2

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Abstract

The protein α-synuclein (αsyn) forms pathologic aggregates in a number of neurodegenerative diseases including Lewy body dementia (LBD) and Parkinson’s disease (PD). It is unclear why diseases such as LBD may develop widespread αsyn pathology, while in Alzheimer’s disease with amygdala restricted Lewy bodies (AD/ALB) the αsyn aggregates remain localized. The amygdala contains αsyn aggregates in both LBD and in AD/ALB; to understand why αsyn pathology continues to progress in LBD but not in AD/ALB, tissue from the amygdala and other regions were obtained from 14 cases of LBD, 9 cases of AD/ALB, and 4 controls for immunohistochemical and biochemical characterization. Utilizing a panel of previously characterized αsyn antibodies, numerous unique pathologies differentiating LBD and AD/ALB were revealed; particularly the presence of dense neuropil αsyn aggregates, astrocytic αsyn, and αsyn-containing dystrophic neurites within senile plaques. Within LBD, these unique pathologies were predominantly present within the amygdala. Biochemically, the amygdala in LBD prominently contained specific carboxy-truncated forms of αsyn which are highly prone to aggregate, suggesting that the amygdala may be prone to initiate development of αsyn pathology. Similar to carboxy-truncated αsyn, it was demonstrated herein that the presence of aggregation prone A53T αsyn is sufficient to drive misfolding of wild-type αsyn in human disease. Overall, this study identifies within the amygdala in LBD the presence of unique strain-like variation in αsyn pathology that may be a determinant of disease progression.

Highlights

Aggregates comprised of the pre-synaptic neuronal protein, α-synuclein, are the major component in Lewy body (LB) inclusions that pathologically define Parkinson’s disease (PD) and Lewy body dementia (LBD) [52, 96]; 40–60% of Alzheimer’s disease (AD) cases display LBs that are most commonlySorrentino et al Acta Neuropathologica Communications (2019) 7:142 which may influence the tendency of the protein to misfold and aggregate; in disease, 90% or more of αsyn becomes phosphorylated at Ser129 and 10–20% may become carboxy (C)-terminally truncated within LB enriched extracts [2, 4, 53, 60, 62]
This study aims to define the biochemical and immunohistochemical differences in the intrinsic nature of Lewy related pathology (LRP) within the amygdala in LBD compared with amygdala predominant LB pathology (AD/ ALB) to reveal the molecular alterations in pathologic αsyn aggregates associated with pathology that remains localized in amygdala restricted Lewy bodies (AD/ALB) but not LBD
In order to test the theory that an aggregation prone form of αsyn could induce endogenous physiologic αsyn to form pathologic inclusions, sections of hippocampus and midbrain were obtained from a Contursi kindred patient in which familial PD/LBD developed due to a heterozygous A53T mutation in the SNCA gene [27]

Summary

Introduction

Aggregates comprised of the pre-synaptic neuronal protein, α-synuclein (αsyn), are the major component in Lewy body (LB) inclusions that pathologically define Parkinson’s disease (PD) and Lewy body dementia (LBD) [52, 96]; 40–60% of Alzheimer’s disease (AD) cases display LBs that are most commonlySorrentino et al Acta Neuropathologica Communications (2019) 7:142 which may influence the tendency of the protein to misfold and aggregate; in disease, 90% or more of αsyn becomes phosphorylated at Ser129 and 10–20% may become carboxy (C)-terminally truncated within LB enriched extracts [2, 4, 53, 60, 62]. C-terminal truncation of αsyn in particular may be crucial, as these species aggregate even more readily than disease-causal mutant forms of αsyn [16, 40, 41, 71, 72, 90, 93] Another important modulator of αsyn pathology in LBD and AD is concurrent AD pathologic changes such as tau neurofibrillary tangles and Aβ plaques which are present at a moderate to severe stage in the majority of LBD cases and worsen clinical outcomes [43, 44, 97, 100]. The diversity of pathologic presentations of synucleinopathies both between and within disease types has been noted extensively in support of the notion that different “strains” of pathologic αsyn may occur [23, 79, 81]

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