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...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	Acta neuropathologica Ročník 142; číslo 3; s. 399 - 421
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2021 Springer Nature B.V
Predmet:	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
On-line prístup:	Získať plný text
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Popis
Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0001-6322 1432-0533 1432-0533
DOI:	10.1007/s00401-021-02349-5