Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Abstract

In Lewy body (LB) diseases, including Parkinson’s disease (PD), without and with dementia (PDD), dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) patients with LB co-pathology1, α-synuclein (α-Syn) aggregates in neurons as LBs and Lewy neurites (LNs)2, while in multiple system atrophy (MSA), α-Syn mainly accumulates in oligodendrocytes as glial cytoplasmic inclusions (GCIs)3. Here, we report that pathological α-Syn in GCIs and LBs (GCI-α-Syn and LB-α-Syn) are conformationally and biologically distinct. GCI-α-Syn forms more compact structures and is ~1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of MSA. Surprisingly, GCI-α-Syn and LB-α-Syn show no cell type preference in seeding α-Syn pathology, raising the question of why they demonstrate different cell type distributions in LB disease versus MSA. Strikingly, we found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.

Seeding variability of different alpha synuclein strains in synucleinopathies

“…Because α-synuclein aggregates in PD are mainly found in subcortical regions, 33 we investigated whether the seeding activity may depend on the brain region. 35 To explore whether converted and aggregated α-synuclein in DLB brain-seeded RT-QuIC reactions underwent structural changes in a more stable and β-sheet-enriched state conformation, 13 we treated RT-QuIC products with PK. 34 Interestingly, α-synuclein seeding activity could be detected in 75% of DLB cases and in 0% in PD and 0% in control cases (Table; Fig 3C,D).…”

“…7,8 However, DLB displays a higher presence of α-synuclein aggregates in frontal cortex (FCx), reflected in the presence of cognitive dysfunctions in patients, whereas PD shows more prominent aggregates in the substantia nigra pars compacta (SNc), accounting for the earlier onset of the motor symptoms compared to DLB. Interestingly, recent studies 13,14 reported conformational and biological differences between aggregated α-synuclein species in PD and multiple system atrophy (MSA) patients (possessing glial rather than neuronal inclusions), 15 indicating that the cellular environment affects the aggregation process of α-synuclein. Interestingly, recent studies 13,14 reported conformational and biological differences between aggregated α-synuclein species in PD and multiple system atrophy (MSA) patients (possessing glial rather than neuronal inclusions), 15 indicating that the cellular environment affects the aggregation process of α-synuclein.…”

“…19,20 Different spatial organizations of the pathogenic seed, defined as strains, 21 have been proposed to account for the differences in the clinical features of similar neurodegenerative pathologies. 22,23 Akin to prion protein, α-synuclein is suspected to form different strains, 10,13,[24][25][26][27] which may underlie the differences in the pathological features of synucleinopathies. 22,23 Akin to prion protein, α-synuclein is suspected to form different strains, 10,13,[24][25][26][27] which may underlie the differences in the pathological features of synucleinopathies.…”

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

“…Moreover, recent experiments in cell and animal models use preformed SYN fibrils or brain homogenates from human LBD subjects to induce spread of SYN pathology that results in neuron loss and dysfunction as well as motor phenotypes which further supports this theory. Most recently, separate SYN species have been identified that may have different “strain‐like” properties, with certain preparations being additionally capable of cross‐seeding either tau or Aβ and others leading to MSA‐type pathologies . However, the core prion feature of infectivity has not clearly been demonstrated for LBD or AD in humans …”

Special issue “Parkinson’s disease”

“…The existence of α-synuclein strains has also been shown by others (Uchihara et al 2005;Peng et al 2018), although these strains do not always lead to the formation of Lewy pathology (Peelaerts et al 2015;Prusiner et al 2015). The surfaces of different pathogenic strains determine their ability not only to evade elimination but also to interact with the cell membrane and to propagate transsynaptically.…”