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ABSTRACT In Parkinson's disease (PD), conformational changes in the α‐synuclein monomer precede the formation of Lewy bodies. We examined postmortem PD and undiseased (control) substantia nigra for evidence of pathological crosslinking of α‐synuclein by tissue transglutaminase (tTG) using immunohistochemistry, immunoprecipitation, and Western blot. Consistent with previous reports, we found that both tTG and its substrate‐characteristic N ε ‐(γ‐glutamyl)‐lysine crosslink are increased in PD nigral dopamine neurons. Furthermore, both the tTG protein and its substrate crosslink coprecipitated with α‐synuclein in extracts of PD substantia nigra. Unexpectedly, the isodipeptide crosslink was detected in the α‐synuclein monomer as well as in higher molecular mass oligomers of α‐synuclein. Although the intramolecularly crosslinked α‐synuclein monomer was present in control tissue, it was highly enriched in PD substantia nigra. Conversely, significantly less uncrosslinked α‐synuclein remained in the postimmunoprecipitate lysate of PD tissue than in control. Crosslinked α‐synuclein, formed at the expense of the total α‐synuclein monomer, correlated with disease progression. These results demonstrate that much of the α‐synuclein monomer in PD nigra is crosslinked by tTG and thus may be functionally impaired. This modification appears to be an early step in PD pathogenesis, preceding the aggregation of α‐synuclein in Lewy bodies.
Andringa et al. (Thu,) studied this question.