Research Article: Unique α-synuclein pathology within the amygdala in Lewy body dementia: implications for disease initiation and progression

Date Published: September 2, 2019

Publisher: BioMed Central

Author(s): Zachary A. Sorrentino, Marshall S. Goodwin, Cara J. Riffe, Jess-Karan S. Dhillon, Yuxing Xia, Kimberly-Marie Gorion, Niran Vijayaraghavan, Karen N. McFarland, Lawrence I. Golbe, Anthony T. Yachnis, Benoit I. Giasson.

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

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.

Partial Text

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]; additionally 40–60% of Alzheimer’s disease (AD) cases display LBs that are most commonly localized to the amygdala [3, 37, 73, 84, 102]. αsyn aggregates are not merely associated with these diseases but in fact can have etiologic roles, whereby aggregation promoting point mutations (A53T in particular) in the SNCA gene encoding αsyn have been discovered to cause familial PD/LBD [15, 20, 83]. It is unclear what factors prompt physiologic αsyn to misfold and form pathologic inclusions, however once formed these aggregates are key to disease progression as they can likely spread between cells and induce further pathology along with resultant cellular toxicity in a prion-like fashion [21, 54, 103, 110]. Prominent in synucleinopathies is the occurrence of post-translational modifications of αsyn 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]. Tau and Aβ purportedly harbor prion-like properties similarly to αsyn and have in-vitro demonstrated the capacity to cross-seed αsyn aggregation [32, 38, 77, 95] which may be evidenced in human disease by lesions containing both misfolded tau and αsyn within the same cell; these co-localized aggregates are often within the medial temporal lobe (MTL) of LBD patients [33, 46, 49, 88].

The amygdala may be uniquely prone to pathologic developments in a number of neurodegenerative diseases [73]. Exemplifying this, neuritic senile plaques containing Aβ, tau, and αsyn demonstrate the propensity for pathologic aggregation to occur within the amygdala (Fig. 8). Other studies have noticed unique relationships between the amygdala and αsyn; for example, injections of pre-formed αsyn fibrils into various mouse models at differing locations invariably lead to amygdala pathology [1, 7, 13, 65–67, 78, 91, 94], and the amygdala uniquely displays immense upregulation of αsyn in relation to alcohol and opiate abstinence following addiction [114]. The studies herein demonstrate that pathologic αsyn within the amygdala in LBD is unique both in its immunohistochemical properties and immunoblotting profile which may differentiate aggregated forms of αsyn in LBD from the more innocuous AD/ALB. In particular, the presence of aggregation prone carboxy-truncated forms of αsyn within the amygdala may play an initiating role in the disease process as these species are able to misfold and induce endogenous FL αsyn to also aggregate [93]. Our investigations show using diseased human tissue that endogenous WT αsyn is induced to form pathologic inclusions when driven by the more aggregation prone A53T αsyn [15]; we postulate that a more pernicious form of αsyn (due to truncation or other structural modifications) may play a similar role as A53T αsyn in sporadic synucleinopathies. The early involvement of the amygdala in LBD along with sporadic LRP often being entirely restricted to the amygdala indicates that this brain region has the capacity to initiate αsyn misfolding and suggests that aggregation prone forms of αsyn are present and may originate in this region. It is difficult to identify and isolate the more deleterious forms of αsyn from diseased human brain tissue, but comparative immunohistochemical and immunoblotting αsyn profiles amongst various LBD brain regions and between LBD versus AD/ALB amygdalas indicate that there is in fact unique pathological forms of αsyn ubiquitous within the LBD amygdala that differs from other brain regions and disease entities.

In summary, the findings of this study first demonstrated that the presence of an aggressive “strain” of αsyn as is the case with A53T αsyn in familial disease is sufficient to start a pathologic cascade incorporating WT naive αsyn. Furthermore, pathologic determinants of progression from isolated LBs within the amygdala to diffuse synucleinopathy were studied which indicated that thread-like neuropil αsyn pathologies including astrocytic αsyn aggregates are more relevant in predicting widespread pathology than the presence of LBs. The amygdala, due to its early involvement in multiple neurodegenerative diseases and unique pathologies discussed herein, is a key location where diverse strains of misfolded αsyn resulting in detrimental neuropil aggregates are likely to occur.

 

Source:

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