Synuclein Ser129 phosphorylation

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Hideo Fujiwara, Masato Hasegawa, Takeshi Iwatsubo (last author) and colleagues at the University of Tokyo, with Eliezer Masliah, Matthew Goldberg and Jie Shen (2002); John Anderson and colleagues at Elan Pharmaceuticals (2006); Sato, Arawaka, Kato and colleagues at Yamagata University (2011). Funders were not checked.

What happened

Normal brain alpha-synuclein carries few chemical modifications. Fujiwara's team used mass spectrometry and an antibody specific to phosphorylated serine 129 (pS129) on human dementia-with-Lewy-bodies tissue, and showed this site is "selectively and extensively phosphorylated" in the abnormal deposits of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. They also found that the tag promoted fibril formation in vitro. Nature Cell Biology 4:160–164, 2002. Integrity note: Masliah is a middle author. Alzforum's October 2024 report on the Masliah dossier lists this paper among those under scrutiny, with senior author Iwatsubo defending it in the comments; I found no correction, expression of concern or retraction for it (checked 19 Oct 2026). The central finding has independent support: Anderson 2006 (Elan, a company that co-authored papers with Masliah) and Sato 2011 (Yamagata, no Masliah link seen) found the same Ser129 enrichment in Lewy-body synuclein. In 2006 Anderson's group (J Biol Chem 281:29739–29752) inventoried the forms of synuclein in Lewy bodies and found a single phosphorylation at Ser129 was the predominant modification, with small amounts also present in normal and diseased soluble brain extract. Sato 2011 states that about 90% of synuclein deposited in Lewy bodies is phosphorylated at Ser129, against only 4% of total synuclein in normal brain (the abstract gives the figures without a citation).

Why it moved us toward a cure

An antibody specific to pS129 gave researchers a way to stain pathological synuclein, and the tag pointed to the kinases and phosphatases that add and remove it as possible drug targets. It connects to the Lewy-body findings in landmark 5 and the spread models in landmark 43.

Outcome

Open. Is the tag a cause or a consequence? In flies, producing pS129 raised toxicity (Chen & Feany 2005). In rats, blocking the tag (S129A) made synuclein more toxic and a tag-mimicking change (S129D) caused no cell loss (Azeredo da Silveira 2009), whereas adding the kinase GRK6 to A53T synuclein made far more phosphorylated synuclein and worsened dopamine-neuron loss, and the S129A change did not alter the pace (Sato 2011). In mice, an agent that raises activity of the phosphatase PP2A, which strips the tag, cut synuclein phosphorylation and aggregation and improved motor performance (Lee 2011). The question is unsettled. No drug aimed at this step was checked. The layered Lewy-body structure with pS129 at its rim is mentioned in landmark 91.

Sources

• Fujiwara et al., Nat Cell Biol 2002;4:160–164, DOI 10.1038/ncb748
• Anderson et al., J Biol Chem 2006;281:29739–29752, DOI 10.1074/jbc.M600933200, PMID 16847063
• Chen & Feany, Nat Neurosci 2005;8:657–663, DOI 10.1038/nn1443, PMID 15834418
• Azeredo da Silveira et al., Hum Mol Genet 2009;18:872–887, DOI 10.1093/hmg/ddn417, PMID 19074459
• Sato et al., J Neurosci 2011;31:16884–16894, DOI 10.1523/JNEUROSCI.3967-11.2011, PMID 22090514
• Lee et al., J Neurosci 2011;31:6963–6971, DOI 10.1523/JNEUROSCI.6513-10.2011, PMID 21562258
• Fayyad et al., Neurosci Lett 2020;725:134899, DOI 10.1016/j.neulet.2020.134899, PMID 32156613 (studies have "failed to reach a consensus" on whether the tag speeds or slows aggregation, while pS129 is a reliable marker of aggregates)
• Alzforum, "Data fabrication ousted NIA neuroscience director Eliezer Masliah" (dossier; Fujiwara 2002 discussed)
• Not yet verified: the primary source of the 90% and 4% figures (Anderson's abstract does not state them and its full text was not readable); which kinases dominate in human brain; any clinical programme targeting this step.