Figure 6.

Model of progressive changes in αSYN and morphological lesions. This model suggests sequential changers in αSYN and morphological lesions that occur in vulnerable neurons of the substantia nigra and nucleus basalis of Meynert. This model may not apply to all neurons dying as it is not known if all neurons develop these lesions prior to their death. This model posits an unknown initiating factor(s, gray box) that begins a cascade of changes in different pathways over time whose elucidation should be a goal. The model does not speculate if the changes identified are adverse, protective or incidental. Genetic background and mutations may modify the pathway by increasing the expression of flαSYN or increasing the rate of phosphorylation and/or truncation of αSYN. The model suggests where specific interventions may act in the pathway to alter its course (colored arrows). The earliest changes observed were in the level of and distribution of UB, an increase in the cellular level of flαSYN and the formation of an aggregate in the axon hillock of a TH+ neuron. The significance of these early changes is not clear. Subsequently, the expression of pαSYN occurs in the cell body, neurites and axons, followed by the production of tαSYN leading to aggregation and the formation of different lesions. Cell death may be unrelated to the αSYN pathway and the lesions observed.