Parkinson's Disease Is Not Simply a Prion Disorder

Abstract

The notion that prion-like spreading of misfolded α-synuclein (α-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.Dual Perspectives Companion Paper: Prying into the Prion Hypothesis for Parkinson's Disease, by Patrik Brundin and Ronald Melki.

Keywords: aging; alpha-synuclein; calcium; mitochondria; neurodegeneration; neuron; selective vulnerability; synapse.

Figure 1.

Top, The selective regions containing LP and the severity and conceptual progression based on cross-sectional postmortem data from patients at different stages of Parkinson's disease. Bottom, The selective regions with neuronal cell loss, and the severity and conceptual progression based on cross-sectional postmortem data from patients at different stages of PD. Although there is some overlap in the regions identified with LP and neuronal loss, the severity and regions affected over the disease course indicate different progression patterns, and these patterns are independent of the major projections of the regions affected, suggesting that prion propagation through neuronal connections is unlikely as a simplistic mechanism. IL, Intralaminar thalamus; SNd, dorsal tier of the substantia nigra pars compacta; dv, dorsal motor nucleus of the vagus nerve; iz, intermediate reticular zone.

Figure 2.

Schematic summary of the factors potentially driving LP and neurodegeneration in PD. The vulnerable neuronal phenotype has a long, highly branched axon, which could lead to elevated expression of α-SYN, as well as increase transmission sites for misfolded α-SYN. Both of these factors could promote α-SYN aggregation, oligomer formation, LP, and possibly neurodegeneration. In parallel, pacemaking, elevated cytosolic Ca²⁺, and mitochondrial oxidant stress could put vulnerable neurons at risk, both by promoting mitochondrial and lysosomal dysfunction with aging as well as by promoting α-SYN aggregation (through elevated ROS/RNS, Ca²⁺, and calpain activation, proteostatic deficits). Other potential factors, such as a reactive neurotransmitter (e.g., dopamine), also could contribute.