Abstract
Neuronal ceroid lipofuscinosis (NCL) is the most common childhood-onset neurodegenerative disease. NCL is inevitably fatal, and there is currently no treatment available. Children with NCL show a progressive decline in movement, vision and mental abilities, and an accumulation of autofluorescent deposits in neurons and other cell types. Late-infantile NCL is caused by mutations in the lysosomal protease tripeptidyl peptidase 1 (TPP1). TPP1 cleaves tripeptides from the N-terminus of proteins in vitro, but little is known about the physiological function of TPP1. TPP1 shows wide conservation in vertebrates but it is not found in Drosophila, Caenorhabditis elegans or Saccharomyces cerevisiae. Here, we characterize ddTpp1, a TPP1 ortholog present in the social amoeba Dictyostelium discoideum. Lysates from cells lacking ddTpp1 show a reduced but not abolished ability to cleave a TPP1 substrate, suggesting that other Dictyostelium enzymes can perform this cleavage. ddTpp1 and human TPP1 localize to the lysosome in Dictyostelium, indicating conserved function and trafficking. Cells that lack ddTpp1 show precocious multicellular development and a reduced ability to form spores during development. When cultured in autophagy-stimulating conditions, cells lacking ddTpp1 rapidly decrease in size and are less viable than wild-type cells, suggesting that one function of ddTpp1 could be to limit autophagy. Cells that lack ddTpp1 exhibit strongly impaired development in the presence of the lysosome-perturbing drug chloroquine, and this phenotype can be suppressed through a secondary mutation in the gene that we name suppressor of tpp1− A (stpA), which encodes a protein with some similarity to mammalian oxysterol-binding proteins (OSBPs). Taken together, these results suggest that targeting specific proteins could be a viable way to suppress the effects of loss of TPP1 function.
Highlights
Neuronal ceroid lipofuscinosis (NCL), or Batten disease, is the most common childhood-onset neurodegenerative disease, and it is characterized by a progressive decline in vision, motor skills and mental ability (Jalanko and Braulke, 2009)
Dictyostelium cells that are mutant for tripeptidyl peptidase 1 (TPP1) are less viable than wild-type cells under conditions that induce autophagy, suggesting that TPP1 plays a role in the autophagic process
The authors find that a secondary mutation in the gene that they name suppressor of tpp1– A, which encodes a protein with similarity to a human protein involved in sphingolipid metabolism, can suppress a phenotype that is associated with a lack of ddTpp1, suggesting that perturbing the function of analogous human suppressor genes might ameliorate some of the symptoms induced by mutation of TPP1
Summary
Neuronal ceroid lipofuscinosis (NCL), or Batten disease, is the most common childhood-onset neurodegenerative disease, and it is characterized by a progressive decline in vision, motor skills and mental ability (Jalanko and Braulke, 2009). The disease is inevitably fatal, with death generally occurring within a few years of the onset. Many of the proteins encoded by these genes localize to and/or function in the lysosome (Palmer et al, 2013). Despite this lysosomal association, little is known about how mutations in this set of genes cause the symptoms associated with NCL
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
