Increased expression of lysosomal acid phosphatase in CLN3-defective cells and mouse brain tissue.
Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a neurodegenerative disorder caused by defective function of the lysosomal membrane glycoprotein CLN3. The activity of the lysosomal acid phosphatase (LAP/ACP2) was found to be significantly increased in the cerebellum and brain stem of Cln3-targeted mice during the early stages of postnatal life. Histochemical localization studies revealed an increased LAP/ACP2 staining intensity in neurons of the cerebral cortex of 48-week-old Cln3-targeted mice as compared with controls. Additionally, the expression of another lysosomal membrane protein LAMP-2 was increased in all brain areas. Knockdown of CLN3 expression in HeLa cells by RNA interference also resulted in increased LAP/ACP2 and LAMP-2 expression. Finally in fibroblasts of two juvenile neuronal ceroid lipofuscinosis patients elevated levels of LAP/ACP2 were found. Both activation of gene transcription and increased protein half-life appear to contribute to increased LAP/ACP2 protein expression in CLN3-deficient cells. The data suggest that lysosomal dysfunction and accumulation of storage material require increased biogenesis of LAP/ACP2 and LAMP-2 positive membranes which makes LAP/ACP2 suitable as biomarker of Batten disease.
Pohl
Sandra
S
Department of Biochemistry, Children's Hospital, University Medical Center Hamburg, Hamburg, Germany.
Mitchison
Hannah M
HM
Kohlschütter
Alfried
A
van Diggelen
Otto
O
Braulke
Thomas
T
Storch
Stephan
S
D000135:Acid Phosphatase / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000648:ultrastructure; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism / Q000503:physiopathology; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D015415:Biomarkers; C102229:CLN3 protein, mouse; D052119:Lysosomal-Associated Membrane Protein 2; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D000135:Acid Phosphatase; C520785:Acp2 protein, mouse