Abstract
Palmitoyl Protein Thioesterase 1 (PPT1) is an essential lysosomal protein in the mammalian nervous system whereby defects result in a fatal pediatric disease called Infantile Neuronal Ceroids Lipofuscinosis (INCL). Flies bearing mutations in the Drosophila ortholog Ppt1 exhibit phenotypes similar to the human disease: accumulation of autofluorescence deposits and shortened adult lifespan. Since INCL patients die as young children, early developmental neural defects due to the loss of PPT1 are postulated but have yet to be elucidated. Here we show that Drosophila Ppt1 is required during embryonic neural development. Ppt1 embryos display numerous neural defects ranging from abnormal cell fate specification in a number of identified precursor lineages in the CNS, missing and disorganized neurons, faulty motoneuronal axon trajectory, and discontinuous, misaligned, and incorrect midline crossings of the longitudinal axon bundles of the ventral nerve cord. Defects in the PNS include a decreased number of sensory neurons, disorganized chordotonal neural clusters, and abnormally shaped neurons with aberrant dendritic projections. These results indicate that Ppt1 is essential for proper neuronal cell fates and organization; and to establish the local environment for proper axon guidance and fasciculation. Ppt1 function is well conserved from humans to flies; thus the INCL pathologies may be due, in part, to the accumulation of various embryonic neural defects similar to that of Drosophila. These findings may be relevant for understanding the developmental origin of neural deficiencies in INCL.
Highlights
Infantile Neuronal Ceroids Lipofuscinoses (INCL) belongs to a group of lysosomal storage disorders characterized by the fatal progressive deterioration of the visual and central nervous system, and the accumulation of abnormal autofluorescent storage materials in the brain [1,2]
To examine localization of Ppt1 protein, four chicken/rabbit polyclonal antibodies were generated against different regions of Ppt1 that include both internal sequences and the C-terminus
Results indicate that only when Ppt1 is overexpressed at a high level, or is highly enriched in S2 lysates, can a band be detected at the expected size of approximately 28 kD (Figure S2)
Summary
Infantile Neuronal Ceroids Lipofuscinoses (INCL) belongs to a group of lysosomal storage disorders characterized by the fatal progressive deterioration of the visual and central nervous system, and the accumulation of abnormal autofluorescent storage materials in the brain [1,2]. PPT1 deficiency affects only the development and maintenance of cortical neurons in the nervous system. Microarray studies reveal that changes in gene expression can be detected at 10 week-old post-natal PPT1 knock-out mice brains, a time prior to neurodegenerative symptoms [10]. These findings suggest that the loss of this protein may have embryonic developmental consequences prior to being symptomatic. If PPT1 does have a role during embryonic neurogenesis, the elucidation of the fundamental cellular pathways requiring PPT1 during development will be critical
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.
