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

Abstract：

: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.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

von Kleist L,Ariunbat K,Braren I,Stauber T,Storch S,Danyukova T

doi

10.1016/j.ymgme.2018.09.009

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

196-205

issue

2

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(18)30439-6

journal_volume

126

pub_type

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