Carboxy-terminal truncation and phosphorylation of α-synuclein elongates survival in a prion-like seeding mouse model of synucleinopathy

Pathologic intracellular inclusions formed from polymers of misfolded alpha-synuclein (alpha syn) protein define a group of neurodegenerative diseases termed synucleinopathies which includes Parkinson's disease (PD). Prion-like recruitment of endogenous cellular asyn has been demonstrated to occur in animal models of synucleinopathy, whereby misfolded alpha syn can induce further pathologic alpha syn inclusions to form through a prion-like mechanism. It has been suggested that misfolded alpha syn may assume differing conformations which lead to varied clinical and pathological manifestations of disease; this phenomenon bears similarities to that of prion strains whereby the same misfolded protein can produce unique diseases. It is unclear what factors influence the development of unique alpha syn strains, however post-translational modifications (PTMs) such as phosphorylation and truncation that are present in misfolded asyn in disease may play a role due to their modulation of biochemical and structural alpha syn properties. Herein, we investigate the prion-like properties of misfolded alpha syn polymers containing either phosphomimetic (S129E) alpha syn, 5 different major carboxy (C)-truncated forms of alpha syn (1-115, 1-119, 1-122, 1-125, and 1-129 alpha syn), or a mixture of these PTM containing alpha syn forms compared to full-length (FL) alpha syn in HEK293T cells and M83 transgenic mice overexpressing A53T asyn. It is demonstrated that upon peripheral intramuscular injection of these C-truncated or S129E alpha syn polymers into M83 mice, prion-like progression and time to disease onset in this mouse model is elongated when any of these PTMs are present, demonstrating that common modifications to the C-terminus of alpha syn present in disease modulates the prion-like seeding properties of alpha syn.