Role of Different Alpha-Synuclein Strains in Synucleinopathies, Similarities with other Neurodegenerative Diseases

Abstract

Misfolded protein aggregates are the hallmark of several neurodegenerative diseases in humans. The main protein constituent of these aggregates and the regions within the brain that are affected differ from one neurodegenerative disorder to another. A plethora of reports suggest that distinct diseases have in common the ability of protein aggregates to spread and amplify within the central nervous system. This review summarizes briefly what is known about the nature of the protein aggregates that are infectious and the reason they are toxic to cells. The chameleon property of polypeptides which aggregation into distinct high-molecular weight assemblies is associated to different diseases, in particular, that of alpha-synuclein which aggregation is the hallmark of distinct synucleinopathies, is discussed. Finally, strategies targeting the formation and propagation of structurally distinct alpha-synuclein assemblies associated to different synucleinopathies are presented and their therapeutic and diagnostic potential is discussed.

Keywords: Alzheimer; Neurodegenerative diseases; Parkinson; ageing; dementia with lewy bodies; huntington; multiple system atrophy; prion; protein misfolding.

Fig.1

Protein misfolding and aggregation into infectious fibrillar assemblies. Native or natively unfolded polypeptide chain (sphere) undergo conformational changes that lead to distinct abnormal (cube or cylinder) forms. The rates depend on the propensity of the polypeptide to populate any given (cube or cylinder) conformation. The abnormal forms are short lived either because they are unstable or sensitive to clearance. According to the “template assistance” model, the abnormal folding intermediates interact with the native form of the infectious protein and convert it into abnormal forms. The distinct abnormal forms of the polypeptide have the ability to interact transiently with like conformers and establish longitudinal or lateral interactions following the “seeded polymerization” model. The oligomeric species are unstable and dissociate because the inter-molecular interactions do not outweigh the entropic cost of binding. Once longitudinal and lateral interactions have been established between abnormal forms of the polypeptide, distinct stable seeds are formed (in brackets). These seeds grow indefinitely from one or both ends by incorporation of like molecules, yielding fibrils of distinct physical properties. The different fibrils can break into smaller fragments because, amongst other things, of Brownian movement. The rate of breakage depends on the number of bonds established between the molecules. Each resulting fragment acts as seed.

Fig.2

Alpha-synuclein strains. Natively unfolded α-syn (3 different conformations are presented), assemble into polymers that look unlike in the electron microscope. One type of polymers has the shape of spaghetti, while another type has the shape of a flat linguine. The two assemblies have distinct limited proteolysis degradation patterns (molecular bar codes) and solid-state NMR spectra (structural fingerprint). The two kinds of polymers made of the same protein have different functional properties (toxicity, binding propensity to cells, seeding capacities and persistence). They imprint their intrinsic structure to the soluble α-syn they recruit in cells. They behave therefore as two distinct strains.