α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

Abstract

Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. The prion strain hypothesis offers a possible explanation for this conundrum. According to this hypothesis, a single protein sequence is able to misfold into distinct amyloid structures that can cause different pathologies. In fact, a growing body of evidence suggests that conformationally distinct α-Syn assemblies might be the causative agents behind different synucleinopathies. In this review, we provide an overview of research on the strain hypothesis as it applies to synucleinopathies and discuss the potential implications for diagnostic and therapeutic purposes.

Keywords: alpha-synuclein; amyloid; conformational strains; prion-like propagation; prions; synucleinopathies.

Figure 1

Graphical representation of the prion strain hypothesis: (A) a natively folded protein can acquire a β-sheet-rich conformation capable of templating misfolding of other native monomers; by incorporating additional monomers, oligomers form that further grow into amyloid fibrils; (B) the same native monomer can adopt various β-sheet-rich conformations; therefore, distinct three-dimensional fibril structures composed of differently folded subunits can arise. Following the prion strain hypothesis, these amyloid fibrils of different conformations affect different parts of the brain in characteristic ways. Proteinaceous inclusions and cellular damage would occur to varying degrees in different areas of the brain (yellow/mild → purple/severe).

Figure 2

Schematic representation of α-Syn inclusion distribution in PD according to Braak staging. Brainstem and cortical Lewy bodies first appear in the lower brainstem and olfactory bulb of PD patients in Braak stages 1 and 2. In stages 3 and 4, Lewy bodies progressively accumulate in higher brainstem regions and in indicated cortex regions. Finally, PD patients in Braak stages 5 and 6 show accumulation of pathological α-Syn deposits throughout the cortex and brainstem. In the cartoon, the colored areas correspond to regions with α-Syn inclusions and neuronal loss, the intensity of which is indicated by the hue (yellow/mild → purple/severe).

Figure 3

Graphical representation of α-Syn deposition patterns during the progression of various synucleinopathies based on conformation. Pathogenic α-Syn can adopt different conformations with different fibril architectures. According to the prion strain hypothesis, each synucleinopathy would be caused by a distinct α-Syn amyloid conformational variant or strain. Each strain has a distinct spreading pattern and associated neuropathology, resulting in different disease phenotypes in the respective patients. Synucleinopathy-specific α-Syn inclusions and cellular damage would accumulate to a characteristic extent in particular areas of the brain over the course of the disease (yellow/mild → purple/severe).

Figure 4

Graphical representation of the prion cloud model. Amyloid aggregates of the same protein may form a wide range of possible fibril or oligomer architectures. In prion and prion-like diseases, there likely exists one abundant major amyloid conformation, which would determine the strain characteristics, as well as a variety of less abundant minor conformations. In cases where a cellular degradation response is implemented against a certain major conformation, minor unaffected conformations may become more prevalent—a process referred to as strain mutation.