Is Parkinson's disease truly a prion-like disorder? An appraisal of current evidence

Abstract

Parkinson's disease (PD) is the world's second most common neurodegenerative disease and most common movement disorder. Characterised by a loss of dopaminergic neurons and the development of intraneuronal inclusions known as Lewy bodies, it has classically been thought of as a cell-autonomous disease. However, in 2008, two groups reported the startling observation of Lewy bodies within embryonic neuronal grafts transplanted into PD patients little more than a decade previously, suggesting that PD pathology can be propagated to neighbouring cells and calling basic assumptions of our understanding of the disease into question. Subsequent research has largely served to confirm this interpretation, pointing towards a prion-like intercellular transfer of misfolded α-synuclein, the main component of Lewy bodies, as central to PD. This shift in thinking offers a revolutionary approach to PD treatment, potentially enabling a transition from purely symptomatic therapy to direct targeting of the pathology that drives disease progression. In this short review, we appraise current experimental support for PD as a prion-like disease, whilst highlighting areas of controversy or inconsistency which must be resolved. We also offer a brief discussion of the therapeutic implications of these discoveries.

Figure 1

Diagram showing the criteria that must be satisfied for a disease to qualify as a prionopathy [19]. The most unique attribute of prion diseases is their transmissibility between individuals via transfer of pathological protein alone.

Figure 2

The seeding hypothesis of prion disease pathogenesis, adapted from [25].

Figure 3

The 6 stages of PD according to the Braak hypothesis. Pathology begins in the enteric nervous system and progresses to the neocortex.

Figure 4

Possible therapeutic strategies to decrease αsyn transmission in PD. This is not an exhaustive representation; see [7, 57, 59].