Is Parkinson's a prion disease?

This is a timely discussion topic given that today Nobel laureate Stanley Prusiner will present the opening keynote lecture at the XVIII WFN World Congress on Parkinson's Disease and Related Disorders on the topic "Do prions cause Parkinson's disease?” Alpha-synuclein (a-syn) aggregation plays a central role in Parkinson’s Disease (PD) neuropathology and the aggregates spread within the central nervous system according to a very predictable pattern (Braak et al., 2002). Recently, a prion-like transmission of α-syn aggregates was proposed to explain this propagation (Brundin et al., 2008). This process is likely to occur in three consecutive steps: i) exit of α-syn template from the donor cell, ii) entry to the recipient cell, and iii) initiation of the nucleation. The notion of a prion-like propagation for misfolded α-syn recently gained support from studies describing the brains of PD patients transplanted with embryonic mesencephalic neurons more than a decade before their deaths (Kordower et al., 2008; Li et al., 2008). The authors reported on the presence of α-syn-containing Lewy Bodies (LB) in the young grafted neurons. A recent follow-up study indicates these LB develop gradually (2% of transplanted dopaminergic neurons display LB in a 12-year old graft and 5% in a 16-year old transplant) and are similar to those found in dopaminergic neurons in the host substantia nigra (ubiquitin- and thioflavin-S-positive and also containing characteristic α-syn immunoreactive fibrillar structures visible in electron micrographs) (Li et al., 2009). Host-to-graft prion-like transmission of α-syn could explain how the formation of LBs is triggered in the grafted cells, but several factors (e.g. oxidative stress, excitotoxicity, host-derived pro-inflammatory factors) could promote α-syn aggregation within the grafted cells (Brundin et al., 2008). Alternatively, these factors facilitate the intercellular transfer of misfolded α-syn between cells. Importantly, Desplats and coworkers recently reported the first evidence for in vivo α-syn cell-to-cell transfer (Desplats et al., 2009). These authors showed that neuronal stem cells transplanted into the hippocampus of transgenic mice expressing human α-syn displayed human α-syn reactivity and even electron-dense inclusion bodies. In contrast to the grafted patients, where many mechanistic possibilities exist, the only rational explanation for these results is direct transmission of human α-syn from the host tissue to the implanted stem cells. Mechanistically, prior cell culture work by Seung Jae Lee and coworkers suggested that α-syn aggregates can be taken up from the extracellular space via endocytosis (Lee et al., 2008).

Regarding the last nucleation step presumed to follow α-syn cell-to-cell transfer according to this prion-like model, Luk and coworkers recently demonstrated that recombinant α-syn fibrils, tranfected using a liposome system into cultured cells overexpressing α-syn, can trigger the misfolding and the aggregation of intracellular α-syn (Lee et al., 2008). This “seeding” effect of exogenous α-syn fibrils leads to the formation of cytoplasmic ubiquitin- and thioflavin-S-positive LB-like inclusions in the recipient cell. Evidence that this nucleation process can occur in vivo is likely to be the next step in the demonstration of the prion hypothesis for α-syn propagation.

Although emerging evidence from several laboratories now indicates that misfolded α-syn can transfer from one neuron to another, both in cell cultures and in brains containing grafted cells, it is still not clear whether this mechanism is operative in PD. Considering that α-syn aggregates appear to spread throughout the brains of people with PD in a gradual and stereotypic fashion, as described by Braak and coworkers (Braak et al., 2002), it is tempting to propose that intercellular α-syn transfer underlies the progression of the neuropathological changes. Whereas no evidence exists for the ability of α-syn aggregates to transit from one individual to another, the possibility that they might move between cells and promote the progression of symptoms cannot be ignored. Continued studies in cell culture and animal models of PD are needed to understand fully the mechanisms underlying intercellular transfer of α-syn. Importantly, if intercellular α-syn transfer plays an important role in PD progression, it may represent a novel therapeutic target which could lead to treatments able to retard disease progression.

  Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O, et al. Characterization of Lewy body pathology in 12- and 16-year old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov Disorder 2009; in revision.