Evidence for similar enzymatic but different cellular generation of pE79-modified α-synuclein in PD and AD mouse models.

The α-synuclein (aSyn) pathology is a predominant feature of synucleinopathies such as Parkinson's disease (PD). Triggers that may induce aSyn aggregation are not completely understood, but include post-translational modifications. One such modification is aSyn truncation exposing the N-terminal glutamine 79 residue that is subsequently converted into pyroglutamate (pE). The pE79-aSyn variant is prone to oligomerisation and thus highly neurotoxic. Here, we used a Thy1-aSyn PD mouse model overexpressing human wild type aSyn to reveal a possible spatial association of aSyn with matrix metalloproteinase-9 (MMP-9) as aSyn-truncating and with isoglutaminyl cyclase (isoQC) as pE-forming enzymes, respectively. We observed a cellular co-localisation of pE79-aSyn with MMP-9 and isoQC in aSyn overexpressing neurons in the substantia nigra. In addition, MMP-9 and GFAP protein expression increased during aging of Thy1-aSyn mice, whereas that of isoQC was reduced. In order to reveal potential cross-disease mechanisms of pE79-aSyn pathology, its cell type-specific appearance and immunohistochemical co-localisation with MMP-9 and isoQC was also evaluated in the tg2576 Alzheimer's disease (AD) mouse model. Here, a different cellular expression pattern with substantial co-localisation of pE79-aSyn with MMP-9, isoQC, QC and aSyn predominantly in amyloid plaque-surrounding astrocytes was detected. Together, these data indicate that the same enzymatic activities, MMP-9 and isoQC, might be involved in the subsequent pE79-aSyn generation in PD and AD mouse models. The cellular origins, however, differ between the mouse models with neuronal expression of aSyn and its modifying enzymes in the PD mouse model and astrocytic expression in the AD mouse model.