Inactivation of dynamin 1 in Cln1−/− mouse brain contributes to declining synaptic pool size

This is the authors' abstract. We don't add key points for this paper.

Lysosomal storage disorders (LSDs) are genetic disorders caused by impaired lysosomal function, which cause accumulation of undigested substrates in the lysosome causing pathogenesis. In the majority of LSDs, neurodegeneration is a devastating manifestation. Neuronal ceroid lipofuscinoses (NCLs), are a group of the most common neurodegenerative LSDs that mostly affect children. Mutations in >13 different genes (called CLNs) underlie various types of NCLs. The infantile NCL (or INCL), one of the most devastating neurodegenerative LSDs, is caused by mutations in the CLN1 gene encoding palmitoyl‐protein thioesterase‐1 (PPT1), a lysosomal depalmitoylating enzyme. Palmitoylation is the only reversible lipid modification, which regulates the function of many proteins, especially in the brain. Moreover, PPT1‐catalyzed depalmitoylation of S‐acylated proteins is essential for their degradation. Thus, PPT1‐deficiency causes lysosomal accumulation of lipid‐modified proteins (constituents of ceroid) leading to INCL. Previously, we reported that in Ppt1‐deficient Cln1−/− mice, which mimic INCL, synaptic vesicle (SV) pool‐size at the nerve terminals progressively decline with age. We found that this defect originates from impaired exocytosis and endocytosis of SV components at the presynaptic membrane impairing neurotransmission. Dynamin1 is a small neuron specific GTPase that plays critical roles in recycling and regenerating fresh SVs. Here we demonstrate that in Cln1−/− mice there is increased phosphorylation of dynamin‐1, which inactivates its GTPase activity required for regeneration of the SVs. Our results uncover an unexpected role of Ppt1 in maintaining dynamin1 activity and suggest inactivation of dynamin 1 in this mouse model of INCL contributes to impaired SV‐regeneration and progressive decline in SV‐pool size. Support or Funding Information This work was supported in full by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .