Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Abstract

Cathepsin F (cat F) is a widely expressed lysosomal cysteine protease whose in vivo role is unknown. To address this issue, 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.

Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

“…This confirms previous inferences based on structural modeling that at least some mutations lead to a loss of enzymatic activity [17]. It is not well understood how cathepsin-F mutations lead to the observed neurodegeneration and intralysosomal storage in type-B-Kufsdisease [17,37]. Similar to cathepsin-D [38], L and B [39], cathepsin-F may also be involved in the degradation of other lysosomal substrates.…”

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

“…Some of these genes also have been implicated in neuronal death in neurological diseases (11,17,60), including CM (33,56). A number of protease inhibitors were expressed on the arrays, including CTLA-2␣ (22), and may represent a host mechanism to limit the damage mediated by proteases, particularly since these proteolytic processes can lead to development of intracerebral hemorrhaging (63), which is an invariable finding in human and murine CM.…”

The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina

“…The new DNA variants were validated as disease causing mutations by a combination of methods that included: direct Sanger sequencing in a new DNA sample, restriction enzymes, co-segregation within the families, absence of the sequence change in 200 control alleles, and bioinformatic tools: Seventy three banked DNA samples still remain genetically uncharacterized and require analysis and molecular screening; this will be done under a systematic WES research protocol using a NCL panel including PPT1/CLN1, TPP1/CLN2, CLN3, CTSD/CLN10 [56,57], DNAJC5/CLN4 [17], and the most recently NCL associated genes: CLN11/GRN [58], CLN12/ATP13A2 [43], CLN13/CTSF [59,60], KCTD7/CLN14 [8], and CLCN6 [61]. As variant clinical phenotypes are increasingly recognized in the NCL disorders, it is difficult to exclude specific genetic loci based on pathologic data.…”