A new study from scientists at Brigham and Women’s Hospital and Harvard Medical School, Università di Padova and Massachusetts General Hospital has now established a role for phosphorylation in the control of α-synuclein neurotoxicity. The group had previously identified Ser129 phosphorylation as a key event in α-synuclein neurotoxicity in a Drosophila model. Ser129 phosphorylation conferred toxicity to α-synuclein without a substantial increase in the number of fibrillar deposits, suggesting that nonfibrillar species of α-synuclein may be neurotoxic.
The latest work shows that α-synuclein is also phosphorylated at Tyr125 in transgenic Drosophila expressing wild-type human α-synuclein and that this tyrosine phosphorylation protects from α-synuclein neurotoxicity in a Drosophila model of Parkinson’s disease. Further, the team found that there was an age-related decrease in Tyr125 phosphorylation in humans (as well as in the transgenic Drosophila) and that this phosphorylation was undetectable in the brains of patients who had dementia with Lewy bodies.
The study, published in the Journal of Clinical Investigation, suggests that the loss of protective tyrosine phosphorylation may predispose to clinically relevant α-synuclein neurotoxicity in human disease.