Alpha synuclein processing by MMP-3 – implications for synucleinopathies

Bluhm A, Schrempel S, Moceri S, Stieler J, Feja M, Schilling S, Schulze A, von Hörsten S, Hartlage-Rübsamen M, Richter F, Roßner S (2022)


Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 434

Article Number: 114020

DOI: 10.1016/j.bbr.2022.114020

Abstract

α-Synuclein (aSyn) is a protein implicated in physiological functions such as neurotransmitter release at the synapse and the regulation of gene expression in the nucleus. In addition, pathological aSyn assemblies are characteristic for a class of protein aggregation disorders referred to as synucleinopathies, where aSyn aggregates appear as Lewy bodies and Lewy neurites or as glial cytoplasmic inclusions. We recently discovered a novel post-translational pyroglutamate (pGlu) modification at Gln79 of N-truncated aSyn that promotes oligomer formation and neurotoxicity in human synucleinopathies. A priori, the appearance of pGlu79-aSyn in vivo involves a two-step process of free N-terminal Gln79 residue generation and subsequent cyclization of Gln79 into pGlu79. Prime candidate enzymes for these processes are matrix metalloproteinase-3 (MMP-3) and glutaminyl cyclase (QC). Here, we analyzed the expression of aSyn, MMP-3, QC and pGlu79-aSyn in brains of two transgenic mouse models for synucleinopathies (BAC-SNCA and ASO) by triple immunofluorescent labellings and confocal laser scanning microscopy. We report a co-localization of these proteins in brain structures typically affected by aSyn pathology, namely hippocampus in BAC-SNCA mice and substantia nigra in ASO mice. In addition, Western blot analyses revealed a high abundance of QC, MMP-3 and transgenic human aSyn in brain stem and thalamus but lower levels in cortex/hippocampus, whereas endogenous mouse aSyn was found to be most abundant in cortex/hippocampus, followed by thalamus and brain stem. During aging of ASO mice, we observed no differences between controls and transgenic mice in MMP-3 levels but higher QC content in thalamus of 6-month-old transgenic mice. Transgenic human aSyn abundance transiently increased and then showed decrease in oldest ASO mice analyzed. Immunohistochemistry revealed a successive increase in intraneuronal and extracellular formation of pGlu79-aSyn in substantia nigra during aging of ASO mice. Together, our data are supportive for a role of MMP-3 and QC in the generation of pGlu79-aSyn in brains affected by aSyn pathology.

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APA:

Bluhm, A., Schrempel, S., Moceri, S., Stieler, J., Feja, M., Schilling, S.,... Roßner, S. (2022). Alpha synuclein processing by MMP-3 – implications for synucleinopathies. Behavioural Brain Research, 434. https://doi.org/10.1016/j.bbr.2022.114020

MLA:

Bluhm, Alexandra, et al. "Alpha synuclein processing by MMP-3 – implications for synucleinopathies." Behavioural Brain Research 434 (2022).

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