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

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

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  • Media type: E-Article
  • Title: A glutaminyl cyclase‑catalyzed α‑synuclein modification identified in human synucleinopathies
  • Contributor: Hartlage‑Rübsamen, Maike [Author]; Bluhm, Alexandra [Author]; Moceri, Sandra [Author]; Machner, Lisa [Author]; Köppen, Janett [Author]; Schenk, Mathias [Author]; Hilbrich, Isabel [Author]; Holzer, Max [Author]; Weidenfeller, Martin [Author]; Richter, Franziska [Author]; Coras, Roland [Author]; Serrano, Geidy E. [Author]; Beach, Thomas G. [Author]; Schilling, Stephan [Author]; von Hörsten, Stephan [Author]; Xiang, Wei [Author]; Schulze, Anja [Author]; Roßner, Steffen [Author]
  • Published: Berlin; Heidelberg: Springer, [2024]
  • Published in: Acta neuropathologica ; 142,3 (2021), Seite 399-421
  • Language: English
  • DOI: 10.1007/s00401-021-02349-5
  • Keywords: Substantia nigra ; Post-translational modification ; Dementia with Lewy bodies ; Animal models ; Glutaminyl cyclase ; α-Synuclein ; Parkinson’s disease
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access
  • Rights information: Attribution (CC BY)