PMID- 35870616
OWN - NLM
STAT- MEDLINE
DCOM- 20220830
LR  - 20220915
IS  - 1872-7549 (Electronic)
IS  - 0166-4328 (Linking)
VI  - 434
DP  - 2022 Sep 26
TI  - Alpha synuclein processing by MMP-3 - implications for synucleinopathies.
PG  - 114020
LID - S0166-4328(22)00288-1 [pii]
LID - 10.1016/j.bbr.2022.114020 [doi]
AB  - 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.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Bluhm, Alexandra
AU  - Bluhm A
AD  - Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, 
      Germany.
FAU - Schrempel, Sarah
AU  - Schrempel S
AD  - Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, 
      Germany.
FAU - Moceri, Sandra
AU  - Moceri S
AD  - Department for Experimental Therapy, University Clinics Erlangen and Preclinical 
      Experimental Center, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054 
      Erlangen, Germany.
FAU - Stieler, Jens
AU  - Stieler J
AD  - Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, 
      Germany.
FAU - Feja, Malte
AU  - Feja M
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, and Center for Systems Neuroscience, 30559 Hannover, Germany.
FAU - Schilling, Stephan
AU  - Schilling S
AD  - Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular 
      Drug Design and Target Validation, 06120 Halle (Saale), Germany; Anhalt 
      University of Applied Sciences, Faculty of Applied Biosciences and Process 
      Engineering, 06366 Kothen, Germany.
FAU - Schulze, Anja
AU  - Schulze A
AD  - Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular 
      Drug Design and Target Validation, 06120 Halle (Saale), Germany.
FAU - von Horsten, Stephan
AU  - von Horsten S
AD  - Department for Experimental Therapy, University Clinics Erlangen and Preclinical 
      Experimental Center, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054 
      Erlangen, Germany.
FAU - Hartlage-Rubsamen, Maike
AU  - Hartlage-Rubsamen M
AD  - Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, 
      Germany.
FAU - Richter, Franziska
AU  - Richter F
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, and Center for Systems Neuroscience, 30559 Hannover, Germany.
FAU - Rossner, Steffen
AU  - Rossner S
AD  - Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, 
      Germany. Electronic address: steffen.rossner@medizin.uni-leipzig.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220721
PL  - Netherlands
TA  - Behav Brain Res
JT  - Behavioural brain research
JID - 8004872
RN  - 0 (alpha-Synuclein)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Brain
MH  - Humans
MH  - Infant
MH  - Matrix Metalloproteinase 3
MH  - Mice
MH  - Mice, Transgenic
MH  - *Synucleinopathies
MH  - *alpha-Synuclein
OTO - NOTNLM
OT  - Glutaminyl cyclase
OT  - Matrix metalloproteinase-3
OT  - Pyroglutamate modification
OT  - Substantia nigra
OT  - Transgenic mouse models
OT  - alpha-synuclein
EDAT- 2022/07/24 06:00
MHDA- 2022/08/31 06:00
CRDT- 2022/07/23 19:25
PHST- 2022/02/23 00:00 [received]
PHST- 2022/07/01 00:00 [revised]
PHST- 2022/07/19 00:00 [accepted]
PHST- 2022/07/24 06:00 [pubmed]
PHST- 2022/08/31 06:00 [medline]
PHST- 2022/07/23 19:25 [entrez]
AID - S0166-4328(22)00288-1 [pii]
AID - 10.1016/j.bbr.2022.114020 [doi]
PST - ppublish
SO  - Behav Brain Res. 2022 Sep 26;434:114020. doi: 10.1016/j.bbr.2022.114020. Epub 
      2022 Jul 21.