Identification of novel α-synuclein assemblies in Lewy body disease

In 2020, the laboratories of Scheres and Goedert used cryo-electron microscopy (Cryo-EM) to report atomic resolutions corresponding to α-synuclein filaments extracted in the detergent Sarkosyl from multiple-system atrophy (MSA) brains. Sarkosyl, a strong anionic denaturing detergent, does not inactivate prion-like templating associated with MSA filaments. Two types of so-called paired filaments were identified that were twisted in a left-handed configuration. Each filament was assembled by two cords of different protofibrils, in total of four distinct MSA-protofibrils. Importantly, two different filaments were identified within one MSA brain, opening for interpretations of regional filament diversity in disease¹.

In that study, filaments were also extracted from Sarkosyl-treated brain homogenates from dementia with Lewy bodies (DLB). However, the DLB filaments were deemed largely incompatible with Cryo-EM analysis because the structures lacked twisted morphologies required for high-resolution helical reconstructions. Twisted filaments provide a 360-degree vantage in single particle analysis compared to rod filaments which offer limited views and incomplete 3-dimensional reconstructions. Though, based on the limited rod analysis, the Authors speculated that the rod α-synuclein assemblies in the DLB lysates appeared different from those in MSA. Now, this same team reports that a minority of Sarkosyl-extracted α-synuclein assemblies from DLB and Parkinson disease (PD) cortical tissues are indeed twisted, and abundant enough for high-resolution Cryo-EM-based structure analysis².

In the new work from Yang et. al., based on the analysis of extracts from frontal cortex or cingulate cortex from a PD case, two PD cases with dementia, and three DLB cases, a single protofibril was identified with ß-strand alignments that only partially overlap with previously reported α-synuclein assemblies. However, the structure did not allow identification of contact sites with putative partnering protofibrils in a parental filament. The majority of filaments in all brain samples were exposed as straight rods, potentially suggesting a partial stability problem (resulting in loss of twist characteristics) under denaturing conditions. Alternatively, rod filaments that lacked twisting may have always lacked twisted morphology and therefore represent a different species that will remain elusive for now. Regardless, with the new structural model, it will be possible to test whether the proposed assembly matches to filaments from other PD and DLB cases, and in other regions of the brain and body vulnerable to Lewy pathology like the substantia nigra, skin, and gut.

The Yang et. al. contribution will likely result in some controversy as to whether α-synuclein assemblies procured from Sarkosyl-extracts resemble physiologically relevant structures driving Lewy body deposition and toxicity. Several past studies, based on amplification from α-synuclein seeds in brain and CSF, have implicated structural differences in α-synuclein filaments between PD and DLB, or even within the same PD or DLB-affected brain in different regions^3–5. Nevertheless, the field is undeniably closer to α-synuclein structures found in patient brain; that is, structures that will facilitate the development of better models of disease as well as therapeutics and ligands that target specific α-synuclein assemblies occurring in disease.