Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation.
Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Li
L
Chen
Magali
M
Periquet
Xu
X
Wang
Alessandro
A
Negro
Pamela J
PJ
McLean
Bradley T
BT
Hyman
Mel B
MB
Feany
D000375:Aging / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000503:physiopathology; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein; D014443:Tyrosine; D012694:Serine