A Drosophila model of Type B Kufs/CLN13 disease to study pathogenesis and Cathepsin F function

Neuronal ceroid lipofuscinoses (NCL) are rare inherited forms of neurodegeneration. Among NCLs, mutations in the human gene CTSF cause CLN13, a disease that develop during adulthood, also known as Type B Kufs disease. CTSF produces Cathepsin F, an enzyme that acts in lysosome to cleave proteins to be degraded. Type B Kufs disease is characterized by variable symptoms that include seizures, dementia and alteration of movement and coordination. A mouse lacking Ctsf is available and recapitulates traits of the disorder, but it does not allow to study functionally patient-specific mutations.

By editing the fruit fly Drosophila melanogaster genome, we have recently generated a model of Type B Kufs disease that reproduces in vivo the neurodegeneration, as well as other alterations observed in patients. These defects are reverted by reintroduction of the Drosophila form of Cathepsin F (CtsF). We also have generated flies carrying 6 different variants of CtsF that correspond to the mutations found in patients.

We now plan to measure the function of each form with respect to neuro-motor deficit and other dis-regulations. In addition, we will assess how the disease develops in the model. Finally, we will investigate how potential substrates of CtsF might contribute to Type B Kufs disease emergence.

Our in vivo study establishes the first patient-centered models of Type B Kufs disease. These will be useful to elucidate the genetic underpinnings of the disease as well as to predict the impact of CtsF mutations, paving the way to future interventions.