Anti-MAN2B1 monoclonal antibody Made to order

alpha-Mannosidosis is a lysosomal storage disorder caused by alpha-mannosidase deficiency. Clinical course of the disease ranges from severe infantile to milder juvenile type and includes mental retardation, skeletal deformities, coarse facies, hepatomegaly and hearing loss. The aim of the study was to analyse mitochondrial ultrastructure and function in cultivated fibroblasts from three patients with alpha-mannosidosis. All patients were homozygous for the c.2248C > T mutation in the MAN2B1 gene encoding lysosomal alpha-mannosidase. The mutation results in incorrect protein folding and severe decrease of alpha-mannosidase activity. The misfolded protein is retained by the control system of endoplasmic reticulum (ER). In analysed fibroblasts, we observed dilated ER, higher amount of aberrant mitochondria and reduced mitochondrial mass compared to controls. Respiratory chain complex IV, cytochrome c oxidase (COX), activity and the ratio between COX and citrate synthase (control enzyme) were significantly increased in comparison to controls (P < 0.05). Furthermore, the activity at least from one of other respiratory chain complexes was increased in each studied cell line. Mitochondrial membrane potential as well as reactive oxygen species production were comparable with controls. Based on our results, we hypothesize more profound effect of swelled and damaged mitochondria and ER dilatation on tissues with higher energy demand than fibroblasts have.

The a-mannosidase activity in human frontal gyrus, cerebrospinal fluid and plasma has been analyzed by DEAE-cellulose chromatography to investigate the origin of the alpha-mannosidase activity in cerebrospinal fluid (CSF). The profile of alpha-mannosidase isoenzymes obtained in CSF was similar to that in the frontal gyrus but different from that in human plasma. In particular the two characteristic peaks of lysosomal alpha-mannosidase, A and B, which have a pH-optimum of 4.5 and are found in human tissues, were present in both the frontal gyms and CSF. In contrast the majority of alpha-mannosidase activity in human plasma was due to the so called intermediate form, which has a pH-optimum of 5.5. The results suggest that the intermediate form of alpha-mannosidase in plasma does not cross the blood-brain barrier and that the alpha-mannosidase activity present in the cerebrospinal fluid is of lysosomal type and of brain origin. Thus the alpha-mannosidase activity in cerebrospinal fluid might mirror the brain pathological changes linked to neurodegenerative disorders such as Parkinson's disease.