Innovita Research Foundation

I.R.F. / Aging news / Diseases / 06032801

Cathepsin F a Candidate for Adult-onset Neuronal Ceroid Lipofuscinosis
Posted on: March 28, 2006

Cathepsin F (cat F) is a widely expressed lysosomal cysteine protease whose in vivo role is unknown. The human genome contains 11 papain-family cysteine proteases, several of which have restricted tissue expression and specific, non redundant functions. Cathepsin F (cat F), known to have widespread tissue mRNA expression, is a relatively understudied member of this enzyme family. Cat F is unique among papain-type cathepsins due to an elongated N-terminal pro-region, which contains a cystatin-like domain attached with a flexible linker to the canonical papain-type catalytic domain. The enzyme contains a typical signal peptide and is found within the endosomal compartment of cells. Several prior studies have demonstrated in vitro that cat F is a potent endoprotease. Recombinant active cat F degrades the major histocompatibility complex (MHC) class II chaperone, invariant chain (Ii), as well or better than cathepsin S (cat S). More recently, cat F has been implicated in lipoprotein biology by virtue of its ability to inhibit cholesterol efflux from peritoneal macrophages in vitro and to degrade apolipoprotein B100 in vitro. However, a physiological role for cat F has not been established. Numerous enzyme deficiencies are accompanied by accumulation of undegraded substrates within lysosomes, resulting in lysosomal storage diseases. Among these are mucopolysaccharidoses, glycoproteinoses, sphingolipidoses, and lipidoses. The neuronal ceroid lipofuscinoses (NCLs) are a collection of diseases involving lysosomal storage manifested by gross accumulation of autofluorescent lipofuscin- like material. The features of NCL include progressive loss of motor skills and vision, mental decline, myoclonus, seizures, and premature death. Notably, the pathological manifestations of NCL are mostly localized to the central nervous system (CNS) without visceral involvement. The identified gene defects linked to NCL characteristically exhibit autosomal-recessive transmission, and most encode proteins that localize to the endosomal/lysosomal compartment. Several of these are lysosomal enzymes, including palmitoyl protein thioesterase 1 (PPT1) and tripeptidyl peptidase 1 (TPP1). Deficiency in cathepsin D (cat D), an aspartyl endoprotease, also results in an NCL-like phenotype, along with more widespread visceral lysosomal abnormalities, as does the engineered mouse model lacking PPT2 activity. However, the identified causes of NCL are largely responsible for disease beginning in infancy or childhood. There is a paucity of genetic information or etiological mechanism available for adult onset NCL, also referred to as Kufs disease. Of the reported murine or human single cysteine cathepsin deficiencies, none have been associated with neuronal lysosomal defects. To address cathepsin F function, mice deficient in cat F were generated via homologous recombination. Although cat F-/- mice appeared healthy and reproduced normally, they developed progressive hind leg weakness and decline in motor coordination at 12 to 16 months of age, followed by significant weight loss and death within 6 months. Cat F was found to be expressed throughout the central nervous system (CNS). Cat F-/- neurons accumulated eosinophilic granules that had features typical of lysosomal lipofuscin by electron microscopy. Large amounts of autofluorescent lipofuscin, characteristic of the neurodegenerative disease neuronal ceroid lipofuscinosis (NCL), accumulated throughout the CNS but not in visceral organs, beginning as early as 6 weeks of age. Pronounced gliosis, an indicator of neuronal stress and neurodegeneration, was also apparent in older cat F-/- mice. Cat F is the only cysteine cathepsin whose inactivation alone causes a lysosomal storage defect and progressive neurological features in mice. The late onset suggests that this gene may be a candidate for adult-onset NCL.

Source: Chi-Hui Tang, Je-Wook Lee, Michael G. Galvez, Liliane Robillard, Sara E. Mole, and Harold A. Chapman; Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease; Molecular And Cellular Biology, Mar. 2006, p. 23092316; Vol. 26, No. 6
< Previous |  Next >