Diagnosis of late-infantile neuronal ceroid lipofuscinosis: A new sensitive method to assay lysosomal pepstatin-insensitive proteinase activity in human and animal specimens by capillary electrophoresis

Abstract

Batten disease, or human late-infantile neuronal ceroid lipofuscinosis (LINCL) is a familiar progressive degenerative disease affecting children, caused by a deficiency of a lysosomal proteinase (tripeptidyl peptidase I, TPP-I) and characterized by the accumulation of autofluorescent storage bodies in the brain and other tissues of the body. Current methodology used to diagnose this disease needs to be improved in order to have less invasive techniques with higher resolution and shorter assay time. In this report, we discuss the potential merits of micellar electrokinetic chromatography as an excellent tool that requires minute samples but offers high resolution and a short running time for monitoring TPP-I activity in human and animal specimens.

Gemfibrozil and Fenofibrate, Food and Drug Administration-approved Lipid-lowering Drugs, Up-regulate Tripeptidyl-peptidase 1 in Brain Cells via Peroxisome Proliferator-activated Receptor α

“…This study also showed the presence of enzyme activity in various animals having NCL-like neurodegenerative symptoms rendering them unsuitable for being a model for classical LINCL (30). Furthermore, using a highly sensitive capillary electrophoresis technique, Viglio et al (8) reported that lymphocytes from patients affected with LINCL exhibited TPP1 activity, although at low levels (in a range between 0.1 and 0.8 milliunits/mg). These findings about the presence of residual enzymatic activity in LINCL patients are very interesting as they indicate the presence of at least a few copies of the functional gene in the system.…”

“…Mouse Primary Astrocytes-There have been reports that residual TPP-I activity can be found in patients indicating that a few copies of normal Cln2 gene are left in patients affected with LINCL (8,9,30,31). We examined if FDA-approved lipid-lowering drugs like gemfibrozil and fenofibrate were capable of up-regulating the expression of TPP1 in brain cells.…”

“…Currently, there is no established treatment or drugs available for this disease; all approaches are merely supportive or symptomatic, indicating a need for novel therapeutic approaches (7). However, there are different variants of Cln2 mutations, and there have been reports that residual TPP-I activity can be found in patients with LINCL, indicating that there must be a few copies of the normal Cln2 gene remaining in patients affected with LINCL (8,9). Thus, one approach for treatment may be to find ways to enhance the levels and residual activity of the TPP1 protein to ameliorate the disease.…”

Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPARα: Implications for late-infantile Batten disease therapy

“…The classic late-infantile form of NCL (LINCL) is characterized by mutations in the Cln2 gene, which encodes a lysosomal enzyme TPP1. Several reports have indicated that residual activity of TPP1 is retained in LINCL (3,20,21) prompting a new field of research directed towards enhancing the function of residual TPP1 under disease scenario. In this study, we demonstrate that HDMB, an endogenous ligand of PPARα, can upregulate TPP1 expression and activity in mouse neuronal cell line and primary brain cells.…”

“…Therefore, at present, there is a requirement for novel, less invasive treatment options for LINCL. Studies have suggested that residual TPP1 activity is retained in LINCL patients, suggesting that a limited number of functional copies of the Cln2 gene are present in these patients (3,20,21). Therefore, drugmediated therapeutic strategies targeted towards augmenting the expression and residual activity of TPP1 could be of potential benefit for LINCL treatment.…”