Insular cortex sub-region-dependent distribution pattern of α-synuclein immunoreactivity in Parkinson’s disease and dementia with Lewy bodies

Abstract

The insular cortex is a heterogeneous and widely connected brain region. It plays a role in autonomic, cognitive, emotional and somatosensory functions. Its complex and unique cytoarchitecture includes a periallocortical agranular, pro-isocortical dysgranular, and isocortical granular sub-regions. In Parkinson's disease (PD), the insula shows α-synuclein inclusions in advanced stages of the disease and its atrophy correlates with cognitive deficits. However, little is known regarding its regional neuropathological characteristics and vulnerability in Lewy body diseases. The aim of this study is to assess the distribution pattern of α-synuclein pathology in the insular sub-regions and the selective vulnerability of its different cell types in PD and dementia with Lewy bodies (DLB). Human post-mortem insular tissues from 10 donors with incidental Lewy body disease (iLBD), PD, DLB, and age-matched controls were immunostained for α-synuclein and glial fibrillary acid protein (GFAP). Results showed that a decreasing gradient of α-synuclein pathology was present from agranular to granular sub-regions in iLBD, PD and PD with dementia (PDD) donors. The agranular insula was heavily inflicted, revealing various α-synuclein immunoreactive morphological structures, predominantly Lewy neurites (LNs), and astroglial synucleinopathy. While dysgranular and granular sub-regions showed a decreasing gradient of inclusions and more Lewy bodies (LBs) in deeper layers. In DLB, this gradient was less pronounced and severe pathology was observed in the granular insula compared to PDD and regardless of disease stage.Protoplasmic astrocytes showed α-synuclein inclusions and severe degenerative changes increasing with disease severity. While few von Economo neurons (VENs) in the fronto-insular region revealed inclusions, particularly in PDD patients. Our study reports novel findings on the differential involvement of the insular sub-regions in PD and particular involvement of the agranular sub-region, VENs and astrocytes. Thus, the differential cellular architecture of the insular sub-regions portrays the topographic variation and vulnerability to α-synuclein pathology in Lewy body diseases.

A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity

“…This suggests that the remodeling of the newly seeded fibrils into LB-like inclusions of distinct morphologies is driven not only by the structure of the PFF seeds but also by neuronal cell type-dependent properties. These findings are consistent with the immunohistochemical-based studies that revealed that the morphology of the LBs varies according to their location in human brain tissues from PD and synucleinopathies (17,44,50,72,73). Last, at D21, the level of LN-like pathology detected in E83Q PFF-treated neurons was higher than that in the mouse PFF-treated neurons (Fig.…”

“…Consistent with previous findings, in cortical neurons, both endogenous aSyn and seeding activity levels are much lower than in hippocampal neurons. Therefore, our data suggest that intrinsic cellular properties, other than the endogenous level of aSyn or its misfolded properties, contribute to the cellular vulnerability to LB pathology formation and maturation, as also suggested in human synucleinopathies (72,73). Together, our findings demonstrate that in the primary neuronal seeding model, human PFFs generated from E83Q aSyn could (i) overcome the reported species barrier (36,37) and (ii) enhance the capacity of the human PFFs to trigger the de novo formation of pS129-positive fibrils capable of converting into LB-like inclusions.…”

A novel mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein fibrils and recapitulates its pathological diversity

“…This suggests that the remodeling of the newly seeded fibrils into LB-like inclusions of distinct morphologies is driven not only by the structure of the PFF seeds but also by neuronal-cell type-dependent properties. These findings are consistent with the immunohistochemicalbased studies that revealed that the morphology of the LBs varies according to their location in human brain tissues from PD and synucleinopathies (26,69,100,101,108,113). Finally, at D21, the level of LN-like pathology detected in E83Q PFFs-treated neurons was higher than that of the mouse PFF-treated neurons (Fig.…”

“…Consistent with previous findings, in cortical neurons, both endogenous aSyn and seeding activity levels are much lower than in hippocampal neurons. Therefore, our data suggest that intrinsic cellular properties, other than the endogenous level of aSyn or its misfolded properties, contribute to the cellular vulnerability to LB pathology formation and maturation, as also suggested in human synucleinopathies (100,101). Altogether, our findings demonstrate that in the primary neuronal seeding model, human PFFs generated from E83Q aSyn could: 1) overcome the reported species barrier (53,54); and 2) enhance the capacity of the human PFFs to trigger the de novo formation of pS129-positive fibrils capable of converting into LB-like inclusions…”