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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:93686 |
| Date | 11 September 2024 |
| Creators | 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 |
| Publisher | Springer |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.1007/s00401-021-02349-5 |
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