A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix...

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Published in:Acta neuropathologica Vol. 142; no. 3; pp. 399 - 421
Main Authors: Hartlage-Rübsamen, Maike, Bluhm, Alexandra, Moceri, Sandra, Machner, Lisa, Köppen, Janett, Schenk, Mathias, Hilbrich, Isabel, Holzer, Max, Weidenfeller, Martin, Richter, Franziska, Coras, Roland, Serrano, Geidy E., Beach, Thomas G., Schilling, Stephan, von Hörsten, Stephan, Xiang, Wei, Schulze, Anja, Roßner, Steffen
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2021
Springer Nature B.V
Subjects:
alpha-Synuclein - metabolism
Alzheimer's disease
Aminoacyltransferases - metabolism
Animals
Axons
Brain - pathology
Cell size
Cell Survival
Cell viability
Chromatography, Gel
Dementia disorders
Dopamine receptors
Dopaminergic Neurons - metabolism
Electron microscopy
Epitopes
Fibrils
Glutamine
Glutamine - metabolism
Humans
Kinetics
Lewy bodies
Lewy Body Disease - genetics
Lewy Body Disease - metabolism
Mass spectroscopy
Matrix metalloproteinase
Medicine
Medicine & Public Health
Mice
Mice, Transgenic
Movement disorders
N-Terminus
Neurodegeneration
Neurodegenerative diseases
Neurons
Neurosciences
Neurotoxicity
Original Paper
Parkinson Disease - genetics
Parkinson Disease - metabolism
Parkinson's disease
Pathology
Protein interaction
Protein Processing, Post-Translational
Proteolysis
Sambucus nigra - cytology
Sambucus nigra - metabolism
Substantia nigra
Synuclein
Synucleinopathies - genetics
Transgenic mice
Post-translational modification
α-Synuclein
Glutaminyl cyclase
Animal models
Substantia nigra
Parkinson’s disease
Dementia with Lewy bodies
ISSN:0001-6322, 1432-0533, 1432-0533
Online Access:Get full text
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Summary:Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.
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ISSN:0001-6322
1432-0533
1432-0533
DOI:10.1007/s00401-021-02349-5