How strong is the evidence that Parkinson's disease is a prion disorder?

Abstract

Purpose of review We describe evidence supporting the hypothesis that α-synuclein has a prion-like role in Parkinson’s disease and related α-synucleinopathies, and discuss how this novel thinking impacts the development of diagnostics and disease-modifying therapies. Recent findings Observations that immature dopamine neurons grafted to Parkinson’s disease patients can develop Lewy bodies triggered a surge of interest in the putative prion-like properties of α-synuclein. We recount results from experiments which confirm that misfolded α-synuclein can exhibit disease-propagating properties, and describe how they relate to the spreading of α-synuclein aggregates in α-synucleinopathies. We share insights into the underlying molecular mechanisms and their relevance to novel therapeutic targets. Finally, we discuss what the initial triggers of α-synuclein misfolding might be, where in the body the misfolding events might take place and how this can instruct development of novel diagnostic tools. We speculate that differences in anatomical trigger sites and variability in α-synuclein fibril structure can contribute to clinical differences between α-synucleinopathies. Summary The realization that α-synuclein pathology can propagate between brain regions in neurodegenerative diseases has deepened and expanded our understanding of potential pathogenic processes which can lead to the development of novel diagnostic tools as well as the identification of new therapeutic targets.

Neurocognitive and psychiatric disorders‐related axonal degeneration in Parkinson's disease

“…These results are in line with the findings of some resting-state functional MRI studies, which have demonstrated alterations in resting-state brain activity in the default mode network that consists of the precuneus/posterior cingulate cortex; medial prefrontal cortex; and medial, lateral, and inferior parietal cortex in PD patients with NCPs (Hu et al, 2015;Jia, Li, Li, Liang, & Fu, 2018;Shin et al, 2017;van Eimeren, Monchi, Ballanger, & Strafella, 2009). The fact that PD pathology progresses from the anterior to the posterior parts of the WM (Braak & Del Tredici, 2008;Brundin, Ma, & Kordower, 2016) partially explains the findings of this study.…”

Parkinson disease

“…). α‐synuclein tends to spread through neurons in a prion‐like manner, and this mechanism of transmission probably underlies the progression of pathological alterations previously described . Furthermore, some data suggest that α‐synuclein aggregation may begin in the autonomic plexi of the gut and spread rostrally and that this could be influenced by the gut microbiome .…”

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

“…Studies on experimental models of PD have confirmed the occurrence of trans-synaptic transmission of pathological α -synuclein in vivo [17–20]. In light of evidences supporting host-to-graft α -synuclein passage, as well as the ability of the protein to propagate protein misfolding in recipient cells, a “prion-like” hypothesis of PD has been postulated [21–29]. Indeed, prions are transmissible misfolded conformers of the prion protein, PrP, which seed further generation of infectious proteins [30].…”