Drug Discovery Opinion

α-Synuclein, expressed primarily in neural tissue, is normally an unstructured, soluble, protein. Under some circumstances, however, it has the ability to aggregate and form insoluble fibrils. A missense mutation in α-synuclein, A53T, was the first defined genetic lesion in familial Parkinson’s disease. Subsequently, α-synuclein was identified as a major component of Lewy bodies, even in the more common later-onset variant of Parkinson’s, which in most cases does not involve a clear family history of the disease. Lewy bodies are also seen in a group of related disorders, synucleinopathies, which may share important pathways of pathogenesis with Parkinson’s disease.

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.

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