Distinct α-Synuclein strains and implications for heterogeneity among α-Synucleinopathies

Abstract

The deposition of misfolded β-sheet enriched amyloid protein is a shared feature of many neurodegenerative diseases. Recent studies demonstrated the existence of conformationally diverse strains as a common property for multiple amyloidogenic proteins including α-Synuclein (α-Syn). α-Syn is misfolded and aggregated in a group of neurodegenerative diseases collectively known as α-Synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy body, multiple system atrophy and also a subset of Alzheimer's disease patients with concomitant PD-like Lewy bodies and neurites. While sharing the same pathological protein, different α-Synucleinopathies demonstrate distinct clinical and pathological phenotypes, which could result from the existence of diverse pathological α-Syn strains in patients. In this review, we summarized the characteristics of different α-Synucleinopathies and α-Syn strains generated with recombinant α-Syn monomers. We also make predictions of α-Syn strains that could potentially exist in patients based on the knowledge from other amyloid proteins and the clinical and pathological features of different α-Synucleinopathies.

Keywords: Dementia with Lewy body; Multiple system atrophy; Parkinson's disease; Protein aggregates; α-Synuclein strains; α-Synucleinopathy.

Figure 1. α-Synuclein aggregations in different α-Synucleinopathies

(A) Structural features of α-Synuclein. The N-terminal, NAC and C-terminal domain are highlighted in blue, yellow and green squares respectively. The five PD-related point mutations (A53T, A30P, E46K, H50Q, G51D) are marked in red. The seven hexameric motifs are underlined in purple. (B) α-Synuclein aggregations strained by anti-α-Synuclein antibody (303) in different α-Synucleinopathies. PD: Parkinson’s disease; SN: Substantia nigra; DLB: dementia with Lewy body; Ctx: Cortex; MSA: multiple system atrophy; CB: Cerebellum; GCI: Glial cytoplasmic inclusion; NI: Neuronal inclusion; AD: Alzheimer’s disease; Amg: Amygdala; iLB: Incidental LB disease. Scale bar: 25μm.

Figure 2. Different α-Synuclein strains generated from recombinant proteins

De novo generated α-Syn aggregates under physiological salt concentrations have a cylindrical aspect (Strain A), while those obtained under low salt concentrations are flat (Ribbons). Repeat seeding of Strain A fiber lead to the generation of Strain B fiber, which could cross seed tau aggregation in neurons.