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

Behavioural Brain Research Elsevier

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.

Authors with CRIS profile

Sandra Moceri Department of Experimental Therapy Stephan von Hörsten Professur für Experimentelle Biomedizin

Involved external institutions

Universität Leipzig DE Germany (DE) Zentrum für Systemische Neurowissenschaften Hannover (ZSN) / Center for Systems Neuroscience Hannover DE Germany (DE) Fraunhofer-Institut für Zelltherapie und Immunologie (IZI) DE Germany (DE)

How to cite

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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