Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies

Abstract

Protein misfolding is a general hallmark of protein deposition diseases, such as Alzheimer’s disease or Parkinson’s disease, in which different types of aggregated species (oligomers, protofibrils and fibrils) are generated by the cells. Despite widespread interest, the relationship between oligomers and fibrils in the aggregation process and spreading remains elusive. A large variety of experimental evidences supported the idea that soluble oligomeric species of different proteins might be more toxic than the larger fibrillar forms. Furthermore, the lack of correlation between the presence of the typical pathological inclusions and disease sustained this debate. However, recent data show that the β-sheet core of the α-Synuclein (αSyn) fibrils is unable to establish persistent interactions with the lipid bilayers, but they can release oligomeric species responsible for an immediate dysfunction of the recipient neurons. Reversibly, such oligomeric species could also contribute to pathogenesis via neuron-to-neuron spreading by their direct cell-to-cell transfer or by generating new fibrils, following their neuronal uptake. In this Review, we discuss the various mechanisms of cellular dysfunction caused by αSyn, including oligomer toxicity, fibril toxicity and fibril spreading.

Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease

“…A potential and so far speculative explanation could be that Lamp1 protects against α-synuclein in flies by promoting the formation of innocuous aggregates of this protein, which would tend to accumulate as they are not easily degraded and which could also be more easily detected by immunostaining than the soluble forms. In the absence of Lamp1, a larger part of α-synA30P would remain monomeric in the cytoplasm or, more likely, owing to its aggregation properties, form soluble oligomers, which are known to be the more toxic species of this protein [ 27 ].…”

Oligomeropathies, inflammation and prion protein binding

“…As illustrated by Cascella et al (2022) the detection of oligomers in situ is complicated by the lack of methods to detect these species specifically in vivo and in patient tissues, although interesting results have been obtained with α-syn proximity ligation assay ( Roberts et al, 2015 ). Using mouse anti-α-syn antibody appropriately conjugated with activated oligonucleotides by Duolink ® kits, in medulla, midbrain and cingulate cortex from PD subjects, abundant amounts of oligomers were demonstrated ( Roberts et al, 2015 ).…”

“…Alpha-syn fibril polymorphism has been ascertained by cryo-electron microscopy but a clear understanding of the structure of α-synOs is still lacking ( Li et al, 2018 ; Du et al, 2022 ). The antiparallel intermolecular β-sheet structure has been observed in a stable, particularly toxic oligomeric form of α-syn and has been proposed as distinctive of α-synOs toxic species ( Celej et al, 2012 ; Cascella et al, 2022 ).…”

Precision Medicine in Parkinson’s Disease: From Genetic Risk Signals to Personalized Therapy

“…Additional open questions are also concerned with LBs’ pathology: nigrostriatal cell death occurs very early when LBs are not detectable [ 6 ]; LBs do not correlate with symptom severity, and LBs can be incidentally found in the brains of healthy elderly individuals [ 255 , 256 ] or be even absent in some genetic forms of PD [ 257 , 258 ]. Moreover, recent evidence suggests that α-Syn oligomeric species are more toxic than its more aggregated forms [ 259 , 260 , 261 ]. In accordance, α-Syn oligomers differ from LBs in their topographical distribution—the former being more diffuse in the neocortex and the latter more abundant in the brainstem—they are not found in control subjects and correlate with severity of cognitive impairment [ 262 ].…”