Abstract
The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Cln7 is conserved across species suggesting a common function. Here we demonstrate that Cln7 is required for the normal growth of synapses at the Drosophila larval neuromuscular junction. In a Cln7 mutant, synapses fail to develop fully leading to reduced function and behavioral changes with dysregulation of TOR activity. Cln7 expression is restricted to the post-synaptic cell and the protein localizes to vesicles immediately adjacent to the post-synaptic membrane. Our data suggest an involvement for Cln7 in regulating trans-synaptic communication necessary for normal synapse development.
Highlights
The study of early-onset, inherited forms of neurodegenerative disease provides an opportunity to identify how single gene defects lead to neurodegeneration
As there is growing speculation that the synapse is a target of disease in the neuronal ceroid lipofuscinoses (NCLs), we investigated whether Cln[7] functions at the Drosophila neuromuscular junction (NMJ), a model glutamatergic synapse that is routinely used to gain insight www.nature.com/scientificreports into molecular function of proteins associated with human neurological disease[14]
We have utilized Drosophila as a model system to identify an in vivo role for Cln7/MFSD8, the protein whose activity is reduced in late-infantile neuronal ceroid lipofuscinosis, an early onset childhood neurodegenerative disease
Summary
The study of early-onset, inherited forms of neurodegenerative disease provides an opportunity to identify how single gene defects lead to neurodegeneration. Evidence is building that loss of the CLN genes impacts on synapse function, suggesting that they play a common role either within neurons or non-neuronal cells in the development or homeostasis of synapses[2,12,13]. To further investigate potential roles for Cln[7] we have made use of Drosophila where many genes associated with human neurological conditions, including developmental disorders and neurodegenerative diseases, have been identified to have conserved roles[7,14]. We show that a population of Cln7-containing vesicles localizes at the post-synaptic side of the synapse but autophagy is largely intact in the cln[7] mutants and retrograde BMP signaling pathway driving pre-synapse growth functions normally. We show that there is a molecular interaction between Cln[7] and the TOR complex activator, Rheb, which suggests Cln[7] regulates neural development via TOR from a post-synaptic vesicular compartment
Sign-in/Register to view highlights & summary 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.
