α-synuclein is a relatively small (140 amino acids in length), abundant, natively unfolded, soluble protein found in cells throughout the nervous system and is particularly enriched in presynaptic nerve terminals. Abnormal accumulated α-synuclein is the major component of Lewy bodies in α-synuclein-related diseases (synucleinopathies) such as Parkinson's disease and age-related dementia. Dysfunction of α-synuclein remains a common denominator in each of these diseases although synucleinopathies manifest diverse pathological features. Even though previous studies have demonstrated the involvement of nitration in synucleinopathies, the effects of nitrated α-synuclein and the molecular mechanisms underlying its toxicity are still unclear.

Professor Rongqiao He and his colleagues at the Institute of Biophysics, Chinese Academy of Sciences used a non-enzymatic method which mimics physiological processes at neutral pH to generate nitrated α-synuclein and investigated the underlying mechanisms of nitrated α-synuclein-induced cell death.

In their study, nitrated α-synuclein with four 3-nitrotyrosines (Tyr³⁹, Tyr¹²⁵, Tyr¹³³, and Tyr¹³⁶) was obtained non-enzymatically by incubation with nitrite. The nitrated protein existed as a mixture of monomers, dimers, and polymers in solution. The nitrated α-synuclein could induce cell death in a time- and concentration-dependent manner when SH-SY5Y cells (a human neuroblastoma cell line) were incubated with the dimers and polymers. Treatment with anti-integrin α5β1 antibody partially rescued the SH-SY5Y cells from the cell death. Dot blotting and immunoprecipitation revealed that the nitrated protein bound to integrin on the cell membranes. Level of nitric oxide (NO) and calcium-independent inducible NO synthase (iNOS) activity increased during the initial stages of the treatment. The expression of phosphorylated focal adhesion kinase (FAK) decreased in the cells. Subsequently, an increase in caspase 3 activity was observed in SH-SY5Y cells.

Their results provide new information about α-synuclein nitration and insights revealing how nitrative lesions form in synucleinopathies. Their data suggest that the nitration of α-synuclein plays a role in neuronal degeneration.

This work was supported by the China Postdoctoral Science Foundation, the National Science Foundation of China, the Major State Basic Research Development Program of China, and the Chinese Academy of Sciences and published on the latest issue of JOURNAL OF MOLECULAR CELL BIOLOGY as an original research article.