The concept of alpha-synuclein as a prion-like protein: ten years after

Abstract

Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease.

Keywords: Parkinson’s disease; Transmission; α-synuclein, aggregation.

Figure 1:. Mechanisms of α-syn aggregation and propagation.

(Left) Schematic showing presumed contributions of different factors to the development of Parkinson’s disease and demonstrating how they influence various pieces of the pathway to Lewy pathology (Keller et al. 2012). (Right) Schematic of development of Lewy pathology by step-wise progression from potential triggers, proposed entry sites and mechanisms that may promote α-syn aggregation to the resultant effects of such aggregation. In a more likely scenario, the system can use proteostatic clearance successfully to remove aggregates. However, when proteostatic clearance is impaired and α-syn aggregation and accumulation proceeds unchecked, the initial aggregates may be transferred in a ‘prion-like’ manner and may seed further aggregation, resulting in widespread Lewy pathology that contributes to the development of PD and other synucleinopathies.