Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal ceroid lipofuscinosis (Batten disease) encompasses a group of 8 or more inherited lysosomal storage diseases, with an overall frequency of 1 in 12,500 births. All are characterized by progressive blindness and dementia and were initially classified on the basis of age of onset, clinical phenotype and ultrastructural characterization of the storage material as granular osmiophilic deposits, curvilinear bodies or fingerprint bodies. Recent research has shown that the various forms of Batten disease result from mutations in at least 8 genes which code for proteins involved in different aspects of lysosomal protein catabolism. These include palmitoyl:protein thioesterase 1 (CLN1), tripeptidylpeptidase 1 (CLN2), cathepsin D (CLN8), and two membrane proteins of unknown function (CLN3 and CLN5). Biochemically, Batten disease is characterized by the accumulation in neurons and other cells of an autofluorescent pigment which has resisted many attempts at analysis. In this review we attempt to relate our current understanding of the nature of the storage material in Batten disease with this genetic information. We conclude that the 8 genes probably code for proteins which facilitate the degradation of post-translationally modified proteins in lysosomes, suggesting that the turnover of these proteins is highest in cortical neurons.
 ...
PMID:Batten's disease: clues to neuronal protein catabolism in lysosomes. 1074 Feb 17

Neuronal ceroid lipofuscinoses (NCL) are caused by mutations in eight different genes, are characterized by lysosomal accumulation of autofluorescent storage material, and result in a disease that causes degeneration of the central nervous system (CNS). Although functions are defined for some of the soluble proteins that are defective in NCL (cathepsin D, PPT1, and TPP1), the primary function of the other proteins defective in NCLs (CLN3, CLN5, CLN6, CLN7, and CLN8) remain poorly defined. Understanding the localization and network of interactions for these proteins can offer clues as to the function of the NCL proteins and also the pathways that will be disrupted in their absence. Here, we present a review of the current understanding of the localization, interactions, and function of the proteins associated with NCL.
 ...
PMID:Interactions of the proteins of neuronal ceroid lipofuscinosis: clues to function. 2068 Mar 90

Mutations in the gene encoding CLN5 are the cause of Finnish variant late infantile Neuronal Ceroid Lipofuscinosis (NCL), and the gene encoding CLN5 is 1 of 10 genes (encoding CLN1 to CLN9 and cathepsin D) whose germ line mutations result in a group of recessive disorders of childhood. Although CLN5 localizes to the lysosomal compartment, its function remains unknown. We have uncovered an interaction between CLN5 and sortilin, the lysosomal sorting receptor. However, CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment. We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). In addition, we show that the retromer recruitment machinery is also affected by CLN5 depletion, as we found less loaded Rab7, which is required to recruit retromer. Taken together, our results support a role for CLN5 in controlling the itinerary of the lysosomal sorting receptors by regulating retromer recruitment at the endosome.
 ...
PMID:The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal sorting. 2243 21

The neuronal ceroid lipofuscinoses (NCL, also known as Batten disease) is a devastating neurodegenerative diseases caused by mutations in either soluble enzymes or membrane-associated structural proteins that result in lysosome dysfunction. Different forms of NCL were defined initially by age of onset, affected population and/or type of storage material but collectively represent the most prevalent pediatric hereditary neurovisceral storage disorder. Specific gene mutations are now known for each subclass of NCL in humans that now largely define the disease: cathepsin D (CTSD) for congenital (CLN10 form); palmitoyl protein thioesterase 1 (PPT1) for infantile (CLN1 form); tripeptidyl peptidase 1 (TPP1) for classic late infantile (CLN2 form); variant late infantile-CLN5, CLN6 or CLN8 for variant late infantile forms; and CLN3 for juvenile (CLN3 form). Several mouse models of NCL have been developed, or in some cases exist sporadically, that exhibit mutations producing a progressive neurodegenerative phenotype similar to that observed in human NCL. The study of these mouse models of NCL has dramatically advanced our knowledge of NCL pathophysiology and in some cases has helped delineate the function of proteins mutated in human NCL. In addition, NCL mutant mice have been tested for several different therapeutic approaches and as such they have become important pre-clinical models for validating treatment options. In this review we will assess the current state of mouse models of NCL with regards to their unique pathophysiology and how these mice have helped investigators achieve a better understanding of human NCL disease and therapy.
 ...
PMID:Mouse models of neuronal ceroid lipofuscinoses: useful pre-clinical tools to delineate disease pathophysiology and validate therapeutics. 2250 4

The fatal, primarily childhood neurodegenerative disorders, neuronal ceroid lipofuscinoses (NCLs), are currently associated with mutations in 13 genes. The protein products of these genes (CLN1 to CLN14) differ in their function and their intracellular localization. NCL-associated proteins have been localized mostly in lysosomes (CLN1, CLN2, CLN3, CLN5, CLN7, CLN10, CLN12 and CLN13) but also in the Endoplasmic Reticulum (CLN6 and CLN8), or in the cytosol associated to vesicular membranes (CLN4 and CLN14). Some of them such as CLN1 (palmitoyl protein thioesterase 1), CLN2 (tripeptidyl-peptidase 1), CLN5, CLN10 (cathepsin D), and CLN13 (cathepsin F), are lysosomal soluble proteins; others like CLN3, CLN7, and CLN12, have been proposed to be lysosomal transmembrane proteins. In this review, we give our views and attempt to summarize the proposed and confirmed functions of each NCL protein and describe and discuss research results published since the last review on NCL proteins. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".
...
PMID:Cell biology of the NCL proteins: What they do and don't do. 2596 10

The neuronal ceroid lipofuscinoses (NCLs) are a family of neurodegenerative diseases that affect people of all ages and ethnicities, yet many of the associated genes/proteins are not well characterized. Mutations in MFSD8 (major facilitator superfamily domain-containing 8) cause an infantile form of NCL referred to as CLN7 disease. In this study, we revealed the localization and binding partners of an ortholog of human MFSD8 (Mfsd8) in the social amoeba Dictyostelium discoideum. Putative lysosomal targeting motifs are conserved in Dictyostelium Mfsd8, as are several residues mutated in CLN7 disease patients. Mfsd8 tagged with GFP localizes to endocytic compartments, which includes acidic intracellular vesicles and late endosomes. We pulled-down GFP-Mfsd8 and used mass spectrometry to reveal the Mfsd8 interactome during Dictyostelium growth and starvation. Among the identified hits were the Dictyostelium ortholog of human cathepsin D (CtsD), as well as proteins linked to the functions of the CLN3 (Cln3) and CLN5 (Cln5) orthologs in Dictyostelium. To study the function of Mfsd8, we validated a publically available mfsd8- cell line (GWDI Project) and then used this knockout cell line to show that Mfsd8 influences the secretion of Cln5 and CtsD. This information is then integrated into an emerging model describing the molecular networking of NCL proteins in Dictyostelium. In total, this study identifies Dictyostelium as a new model system for studying CLN7 disease.
 ...
PMID:Mfsd8 localizes to endocytic compartments and influences the secretion of Cln5 and cathepsin D in Dictyostelium. 3208 3