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

Medientyp: E-Artikel

Titel: A glutaminyl cyclase‑catalyzed α‑synuclein modification identified in human synucleinopathies

Beteiligte: Hartlage‑Rübsamen, Maike [Verfasser:in]; Bluhm, Alexandra [Verfasser:in]; Moceri, Sandra [Verfasser:in]; Machner, Lisa [Verfasser:in]; Köppen, Janett [Verfasser:in]; Schenk, Mathias [Verfasser:in]; Hilbrich, Isabel [Verfasser:in]; Holzer, Max [Verfasser:in]; Weidenfeller, Martin [Verfasser:in]; Richter, Franziska [Verfasser:in]; Coras, Roland [Verfasser:in]; Serrano, Geidy E. [Verfasser:in]; Beach, Thomas G. [Verfasser:in]; Schilling, Stephan [Verfasser:in]; von Hörsten, Stephan [Verfasser:in]; Xiang, Wei [Verfasser:in]; Schulze, Anja [Verfasser:in]; Roßner, Steffen [Verfasser:in]

Erschienen: Berlin; Heidelberg: Springer, [2024]

Sprache: Englisch

DOI: 10.1007/s00401-021-02349-5

Schlagwörter: Substantia nigra ; Post-translational modification ; Dementia with Lewy bodies ; Animal models ; Glutaminyl cyclase ; α-Synuclein ; Parkinson’s disease

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Beschreibung: Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degenerationof dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed ofaggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation andto 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, contributeto enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kineticcharacteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and massspectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein toform 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 wereco-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 humanα-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synucleinwas shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was aspatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association ofQC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synucleinin human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenicprotein aggregation.

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