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.

Supplemental material for this article may be found at http://mcb.asm.org/.

This study was supported by grants from the National Institutes of Health, HL48261 (H.A.C.), the Sandler Foundation, the Wellcome Trust UK (054606; S.E.M.), and the Batten Disease Support and Research Association.

We thank the families and their physicians for contributing to this study. We thank Guo-Ping Shi for his help with the initial studies of cathepsin F genomic clones, Amos Baruch (Celera Diagnostics) for cat F polyclonal antibodies, Peter T. Ohara (UCSF) for his surgical expertise, and members of Henry J. Ralston III's laboratory (UCSF) for assistance with EM.