Limited cleavage of tau with matrix-metalloproteinase MMP-9, but not MMP-3, enhances tau oligomer formation.
Tauopathies such as Alzheimer's disease or progressive supranuclear palsy are characterized by pathological deposits of aggregated protein tau. It has been shown that truncated tau is present in these deposits, and it was thus hypothesized that truncation of the protein may play a role in pathological aggregation processes. Furthermore, recent findings indicate that pro-aggregatory extracellular tau can be taken up by neurons and induce neurodegeneration. In this study, we investigated the effect of limited proteolysis by matrix-metalloproteinases 3 and 9 (MMP-3, MMP-9) as well as by the proteinases trypsine and Proteinase K (PK) on tau aggregation behavior. We applied single molecule fluorescence techniques to monitor early tau oligomer formation at nanomolar protein concentrations. We observed that tau is a substrate of both MMP-3 and MMP-9, and show that limited proteolysis by MMP-9, but not by MMP-3, PK or trypsine, increases tau oligomer formation. We further characterize tau fragments resulting from limited cleavage, demonstrating a distinct cleavage pattern for both MMP-3 and MMP-9. In summary, our data demonstrate that tau is a substrate of both MMP-3 and MMP-9, and show a differential influence of these enzymes on tau aggregation behavior, implicating a potential role in neurodegeneration.
Interdisziplinäres Zentrum für Palliativmedizin, Klinikum der Universität München, Marchioninistr. 15, 81377 Munich, Germany.
G
G
Nübling
J
J
Levin
B
B
Bader
L
L
Israel
K
K
Bötzel
S
S
Lorenzl
A
A
Giese
D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D059748:Proteolysis; D013050:Spectrometry, Fluorescence; D016875:tau Proteins / Q000378:metabolism*
D010446:Peptide Fragments; D016875:tau Proteins; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9