A newly generated neuronal cell model of CLN7 disease reveals aberrant lysosome motility and impaired cell survival.

TY - JOUR

T1 - A newly generated neuronal cell model of CLN7 disease reveals aberrant lysosome motility and impaired cell survival.

AU - von Kleist, Lisa

AU - Ariunbat, Khandsuren

AU - Braren, Ingke

AU - Stauber, Tobias

AU - Storch, Stephan

AU - Danyukova, Tatyana

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - Journal Article

UR - https://www.sciencedirect.com/science/article/pii/S1096719218304396?via%3Dihub

U2 - 10.1016/j.ymgme.2018.09.009

DO - 10.1016/j.ymgme.2018.09.009

M3 - SCORING: Journal article

C2 - 30301600

VL - 126

SP - 196

EP - 205

JO - MOL GENET METAB

JF - MOL GENET METAB

SN - 1096-7192

IS - 2

ER -