4.6 Article

Alpha synuclein processing by MMP-3-implications for synucleinopathies

Journal

BEHAVIOURAL BRAIN RESEARCH
Volume 434, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.bbr.2022.114020

Keywords

?-synuclein; Pyroglutamate modification; Transgenic mouse models; Matrix metalloproteinase-3; Glutaminyl cyclase; Substantia nigra

Funding

  1. German Research Foundation (DFG) [RO2226/13-1]
  2. Alzheimer Forschungsinitiative e.V. (AFI) [01ED1501B]
  3. German Federal Department of Education, Science, and Technology, BMBF [01ED1501C]
  4. European Union
  5. Johannes und Frieda Marohn Foundation
  6. Pre-doc Award - Research Academy of Leipzig University
  7. [16004]

Ask authors/readers for more resources

This study identifies a novel post-translational modification, pGlu79-αSyn, which promotes oligomer formation and neurotoxicity in synucleinopathies. MMP-3 and QC are implicated in the generation of pGlu79-αSyn in brains affected by αSyn pathology.
alpha-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

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available