The authors note that to induce “profound motor impairments,” the model requires α-synuclein expression levels “in the order of 4–6 times above normal.” They correctly point out that this is “well above the level of α-syn seen in duplication and triplication patients, which is estimated at 1.5- to 2-fold above normal.” While they suggest the difference might be explained by the compressed timescale of the model, this is a critical discrepancy.
This raises the possibility that the model is not triggering the same slow, insidious pathogenic cascade seen in humans but is instead overwhelming the cell’s proteostatic machinery through a gross, artificial overload. Are we studying Parkinson’s disease pathology or simply the generic cellular toxicity of overexpressing any aggregation-prone protein at extremely high levels?
The entire premise of the “double-hit” models (e.g., AAV-α-syn + rotenone) is that a moderate, “pre-symptomatic” level of α-syn (2-3x normal) acts as a susceptibility factor. However, if the “moderate” dose in the rat is defined purely by the absence of overt symptoms and not by a verified, physiologically relevant expression level (e.g., 1.5-2x), these experiments may still be relying on overly high α-syn levels. The concern is that the “second hit” might simply be pushing an already stressed system over the edge, rather than revealing a true synergistic interaction between two relevant pathological processes at human-like levels.
The severe overexpression could be causing toxicity through mechanisms not primary in human PD, such as disrupting general transcription/translation, inducing massive ER stress, or triggering a severe immune response simply due to the high viral load, potentially making the model less specific for α-synuclein-related pathogenesis.
