Abstract: The build-up of misfolded α-synuclein (α-syn) in the central nervous system is the pathological hallmark of a number of neurodegenerative diseases that are known as α-synucleinopathies. These include Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), dementia with Lewy body (LB), multiple system atrophy (MSA), and a subset of Alzheimer’s disease. Growing evidence underscores that the intercellular transmission and amplification of pathological α-syn are critical processes underlying the progression of α-synucleinopathies (Peng et al., 2020), and as such, the study of these processes could lead to the identification of promising therapeutics to mitigate disease progression. Most previous studies have focused solely on pathological seeds in relation to disease progression. However, successful amplification requires two components: the formation of pathological α-syn seeds and the transformation of soluble α-syn to the pathological conformation. The potential effects that soluble α-syn could have on pathological α-syn amplification have not been studied. Although many post-translational modifications (PTMs) have been identified on α-syn, most studies have focused on the effect of PTMs on pathological α-syn initiation, toxicity, or physiological function (He et al., 2021). However, the effects of soluble α-syn PTMs on pathological α-syn amplification remain unknown. In our recent study (Zhang et al., 2023), we focused on how PTMs on soluble α-syn regulate pathological α-syn spread in different diseases and discovered that PTMs on soluble α-syn drastically modulated pathological α-syn in different α-synucleinopathies.