A newly generated neuronal cell model of CLN7 disease reveals aberrant lysosome motility and impaired cell survival
| Autor: | Ingke Braren, Tobias Stauber, Stephan Storch, Khandsuren Ariunbat, Tatyana Danyukova, Lisa von Kleist |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Endosome Cell Survival Endocrinology Diabetes and Metabolism Cell Culture Techniques Motility 030105 genetics & heredity Biology Biochemistry Exocytosis Cell Line 03 medical and health sciences Mice Abstracts 0302 clinical medicine Endocrinology Neuronal Ceroid-Lipofuscinoses Lysosome Genetics medicine Autophagy Animals Naphthyridines Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway 2. Zero hunger Mice Knockout Neurons TOR Serine-Threonine Kinases Membrane Transport Proteins Biological Transport Phenotype Cell biology medicine.anatomical_structure Mutation Lysosomes Immortalised cell line 030217 neurology & neurosurgery |
| Zdroj: | Supportive Care in Cancer Molecular Genetics and Metabolism |
| ISSN: | 1096-7206 |
| Popis: | Mutations in the CLN7/MFSD8 gene encoding the lysosomal membrane protein CLN7 are causative of CLN7 disease, an inherited neurodegenerative disorder that typically affects children. To gain insight into the pathomechanisms of CLN7 disease, we established an immortalized cell line based on cerebellar (Cb) granule neuron precursors isolated from Cln7-/- mice. Here, we demonstrate that Cln7-deficient neuron-derived Cb cells display an abnormal phenotype that includes increased size and defective outward movement of late endosomes and lysosomes as well as impaired lysosomal exocytosis. Whereas Cln7-/- Cb cells appeared to be autophagy-competent, loss of Cln7 resulted in enhanced cell death under prolonged nutrient deprivation. Furthermore, reduced cell survival of Cln7-deficient cells was accompanied by a significantly impaired protein kinase B/Akt phosphorylation at Ser473 during long-term starvation. In summary, our data demonstrate for the first time that the putative lysosomal transporter CLN7 is relevant for lysosome motility and plays an important role for neuronal cell survival under conditions of starvation. |
| Databáze: | OpenAIRE |
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