Triggers, Facilitators, and Aggravators: Redefining Parkinson's Disease Pathogenesis

Abstract

We hypothesize that Parkinson's disease (PD) pathogenesis can be divided into three temporal phases. During the first phase, 'triggers', such as viral infections or environmental toxins, spark the disease process in the brain and/or peripheral tissues. Triggers alone, however, may be insufficient, requiring 'facilitators' like peripheral inflammation for PD pathology to develop. Once the disease manifests, 'aggravators' spur further neurodegeneration and exacerbate symptoms. Aggravators are proposed to include impaired autophagy and cell-to-cell propagation of α-synuclein pathology. We believe clinical trials need to consider these three phases and target potential therapies at the appropriate stage of the disease process in order to be effective.

Keywords: Parkinson’s disease; clinical trials; genetics; inflammation; α-synuclein.

Figure 1:

Schematic of the ‘triggers, facilitators and aggravators’ conceptual framework for redefining PD pathogenesis. We propose that triggers initiate disease pathogenesis during prodromal PD, and facilitators spread pathology to significantly impact the central nervous system. This results in the onset of PD motor symptoms, at which point aggravators continue to exacerbate cell loss and neuropathology, causing worsening symptoms and enabling the emergence of new symptoms. In the schematic, various suspected or validated factors have been positioned along the horizontal axis based approximately on the phase we consider they have the largest effect, and using font size which is roughly proportional to their estimated relative importance in PD pathogenesis.