Parkinson's Disease Is Not Simply a Prion Disorder

Abstract

The notion that prion-like spreading of misfolded ␣-synuclein (␣-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors. Although these factors provide an explanation for the pattern of neuronal loss in PD, they do not readily explain the apparently staged distribution of Lewy pathology in many PD brains, the feature of the disease that initially motivated the spreading hypothesis by Braak and colleagues. While each hypothesis alone has its shortcomings, a synthesis of the two can explain much of what we know about the etiopathology of PD.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…For example, injection of pathogenic “strains” of α-synuclein into one brain region will trigger the spread of α-synuclein to other brain regions (Brundin and Melki, 2017). However, because α-synuclein is a cytoplasmic protein and pathogenic α-synuclein aggregates accumulate intracellularly, the prion-like mechanism does not readily explain how α-synuclein pathology is transferred from one neuron to adjacent neurons (Surmeier et al, 2017b). One potential mechanism involves extracellular vesicles (EVs).…”

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

“…Surmeier and coauthors posited that neurons in the substantia nigra pars compacta and other vulnerable neurons possess common anatomical and physiological properties, which might explain not only the pattern of cell death in PD but also the arrangement of Lewy bodies and neurites (Surmeier et al 2017). Indeed, an elevated vulnerability of substantia nigra pars compacta neurons in PD has long been considered, but other factors that might help connect pathology with functionality are still not verified (Surmeier et al 2017). While work to fill in the gaps of knowledge continues in animal models of PD and in people with PD, we eagerly await a valid biomarker to track progression of pathology in human PD patients.…”

“…The evidence for involvement of dorsal motor nucleus of the vagal nerve in the pathological “network” in PD is worth reviewing. It appears to be both a site of α-syn pathology in PD (Braak et al 2003a) and a nucleus that contains possible vulnerable neurons with long and branched axons (Surmeier et al 2017). More research is needed to verify that neurons within dorsal motor nucleus of the vagal nerve are indeed vulnerable to either cell death, or development of α-syn pathology, or both.…”

“…What these in vivo studies appear to suggest is that aggregated α-syn, and for that matter Lewy pathology, might spread along defined neural tracts or interconnected brain networks. However, this has so far not been corroborated by data from clinical PD cases, and as outlined above, this will be difficult to do unless a sensitive and specific clinical imaging ligand that identifies α-syn aggregates with very high resolution is developed (Surmeier et al 2017). …”

“…Yet these regions often have limited pathology, if any (Surmeier et al 2017). It would appear that Lewy pathology in clinical PD cases may exist in selective cell populations/brain areas, rather than having a widespread presence in the entire brain.…”