Reduced cystatin B activity correlates with enhanced cathepsin activity in progressive myoclonus epilepsy.
BACKGROUND
Loss-of-function mutations in the gene encoding cystatin B (CSTB) underlie an inherited neurodegenerative disorder, progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). CSTB is an inhibitor of several papain-family cysteine proteases, the lysosomal cathepsins. Its physiological function and the molecular pathways leading to the clinical EPM1 phenotype are unknown.


OBJECTIVE
To elucidate the role of CSTB and different cathepsins in pathogenesis of EPM1.


METHODS
We determined the total papain inhibitory (cystatin) and papain-like (cathepsin) activity as well as specific activities of cathepsins B, H, L and S in lymphoblastoid cells of EPM1 patients, carriers and controls.


RESULTS
In EPM1 patients, who express reduced levels of CSTB mRNA, the papain inhibitory activity was significantly decreased or absent. This reduction was correlated with significant increase in general cathepsin activity. The increase in cathepsin B, L and S activities was highly significant, whereas the increase in cathepsin H activity was not.


CONCLUSIONS
This is the first demonstration of cysteine protease activity being regulated by CSTB activity in a biological context. The effects of decreased CSTB activity in EPM1 pathogenesis may, at least in part, be mediated by cathepsins through increased activity of cathepsins S and L.
Rinne
Riitta
R
Department of Forensic Medicine, University of Turku, Finland.
Saukko
Pekka
P
Järvinen
Mikko
M
Lehesjoki
Anna-Elina
AE
D017209:Apoptosis / Q000502:physiology; D002401:Cathepsin B / Q000502:physiology; D056655:Cathepsin H; D056668:Cathepsin L; D002403:Cathepsins / Q000502:physiology*; D055313:Cystatin B; D015891:Cystatins / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism*; D006801:Humans; D020194:Unverricht-Lundborg Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
C524994:CSTB protein, human; D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D055313:Cystatin B; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534126:CTSH protein, human; D056655:Cathepsin H; C028217:cathepsin S