Dataset Information

Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration.

ABSTRACT:

Background

Posttranslational modifications of beta amyloid (A?) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated A?(3-x), generating pE3-A?. Compared to unmodified A?, pE3-A? is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other A? species. To directly investigate pE3-A? formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of A?) mice expressing truncated human A?(3-42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-A? formation in vivo, ETNA mice were intercrossed with tg mice overexpressing human QC (hQC) to generate double tg ETNA-hQC mice.

Results

Expression of truncated A?(3-42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-A?. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-A? formation. Neuropathology in ETNA mice was associated with behavioral alterations. In particular, hyperactivity and impaired acoustic sensorimotor gating were detected. Double tg ETNA-hQC mice showed similar A? levels and expression sites, while pE3-A? were significantly increased, entailing increased astrocytosis and neuronal loss.

Conclusions

ETNA and ETNA-hQC mice represent novel mouse models for QC-mediated toxicity of truncated and pE-modified A?. Due to their significant striatal neurodegeneration these mice can also be used for analysis of striatal regulation of basal locomotor activity and sensorimotor gating, and possibly for DARPP-32-dependent neurophysiology and neuropathology. The spatio-temporal correlation of pE3-A? and neuropathology strongly argues for an important role of this A? species in neurodegenerative processes in these models.

SUBMITTER: Becker A

PROVIDER: S-EPMC3850634 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration.

Becker Andreas A Kohlmann Stephanie S Alexandru Anca A Jagla Wolfgang W Canneva Fabio F Bäuscher Christoph C Cynis Holger H Sedlmeier Reinhard R Graubner Sigrid S Schilling Stephan S Demuth Hans-Ulrich HU von Hörsten Stephan S

BMC neuroscience 20131001

<h4>Background</h4>Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated Aβ(3-x), generating pE3-Aβ. Compared to unmodified Aβ, pE3-Aβ is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other Aβ species. To directly investigate pE3-Aβ formation an ...[more]

PMID: 24083638

Similar Datasets

Project description:The breakdown of plant biomass to simple sugars is essential for the production of second-generation biofuels and high-value bioproducts. Currently, enzymes produced from filamentous fungi are used for deconstructing plant cell wall polysaccharides into fermentable sugars for biorefinery applications. A post-translational N-terminal pyroglutamate modification observed in some of these enzymes occurs when N-terminal glutamine or glutamate is cyclized to form a five-membered ring. This modification has been shown to confer resistance to thermal denaturation for CBH-1 and EG-1 cellulases. In mammalian cells, the formation of pyroglutamate is catalyzed by glutaminyl cyclases. Using the model filamentous fungus Neurospora crassa, we identified two genes (qc-1 and qc-2) that encode proteins homologous to mammalian glutaminyl cyclases. We show that qc-1 and qc-2 are essential for catalyzing the formation of an N-terminal pyroglutamate on CBH-1 and GH5-1. CBH-1 and GH5-1 produced in a Δqc-1 Δqc-2 mutant, and thus lacking the N-terminal pyroglutamate modification, showed greater sensitivity to thermal denaturation, and for GH5-1, susceptibility to proteolytic cleavage. QC-1 and QC-2 are endoplasmic reticulum (ER)-localized proteins. The pyroglutamate modification is predicted to occur in a number of additional fungal proteins that have diverse functions. The identification of glutaminyl cyclases in fungi may have implications for production of lignocellulolytic enzymes, heterologous expression, and biotechnological applications revolving around protein stability. Pyroglutamate modification is the post-translational conversion of N-terminal glutamine or glutamate into a cyclized amino acid derivative. This modification is well studied in animal systems but poorly explored in fungal systems. In Neurospora crassa, we show that this modification takes place in the ER and is catalyzed by two well-conserved enzymes, ubiquitously conserved throughout the fungal kingdom. We demonstrate that the modification is important for the structural stability and aminopeptidase resistance of CBH-1 and GH5-1, two important cellulase enzymes utilized in industrial plant cell wall deconstruction. Many additional fungal proteins predicted in the genome of N. crassa and other filamentous fungi are predicted to carry an N-terminal pyroglutamate modification. Pyroglutamate addition may also be a useful way to stabilize secreted proteins and peptides, which can be easily produced in fungal production systems.

Dataset Information

Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration.

Background

Results

Conclusions

Publications

Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets