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2018 BDSRA Storch CLN7
1. CLN7
disease
Using mouse models to develop new therapies for CLN7 disease
PI: PD Dr. Stephan Storch, Dr. Tatyana Danyukova, cand. med. Khandsuren Ariunbat
Children’s Hospital, Section Biochemistry, University Medical Center Hamburg-Eppendorf, Germany
Financial support from the German Research Foundation (DFG), the Research Training Group 1459 (GRK1459), the
Batten Disease Support and Research Association (BDSRA) and the European Union (BATCure) is acknowledged.
This project has received funding from the European Union's Horizon 2020 research and innovation programme under
grant agreement No 666918 (www.batcure.eu).
Contact: Phone +49 40 7410 5 1967, E-mail storch@uke.de
www.uke.de/kliniken-institute/kliniken/kinder-und-jugendmedizin/forschung/sektion-biochemie/index.html
Conclusions
• Our mouse model recapitulates key features of human
CLN7 disease
• Loss of Cln7 in mice leads to lysosomal dysfunction in the
brain and the retina
• Quantitative proteomic studies on Cln7 ko lysosomes
revealed depletion of multiple soluble lysosomal proteins
indicating that the loss of functional Cln7 affects the soluble
lysosomal proteome
• Our results suggest that the activation of lysosomal
biogenesis, function and autophagy by small molecules (e.
g. TFEB activators) might be a therapeutic option for the
treatment of CLN7 disease
• CLN7 disease, variant late-infantile phenotype is caused by mutations
in the MFSD8/CLN7 gene
• more than 35 mutations in MFSD8/CLN7 have been identified in CLN7
patients with variant late infantile phenotype
• MFSD8/CLN7 encodes a lysosomal membrane protein of unknown
function
Aim of the studies
Analysis of CLN7 function and test of experimental
therapies using a knockout (KO) mouse model for CLN7
disease
Recent publications:
Brandenstein L, Schweizer M, Sedlacik J, Fiehler J, Storch S. (2016)
Lysosomal dysfunction and impaired autophagy in a novel mouse model
deficient for the lysosomal membrane protein Cln7. Hum. Mol. Genet.
25:777-791.
Jankowiak W, Brandenstein L, Dulz S, Hagel C, Storch S, Bartsch U.
(2016) Retinal degeneration in mice deficient in the lysosomal membrane
protein CLN7. Invest. Ophthalmol. Vis. Sci. 57: 4989-4998.
Danyukova, T., Ariunbat , K., Thelen, M., Brocke-Ahmadinejad, N.,
Mole, S.E., Storch, S. (2018) Loss of CLN7 results in depletion of
soluble lysosomal proteins and impaired mTOR reactivation. Hum. Mol.
Genet., 27: 1711-1722.
Since CLN7 represents an integral membrane protein, enzyme replacement is not an option for the
treatment of CLN7 disease. The BATCure consortium (http://www.batcure.eu/home_page) will focus
on developing treatments for CLN7 disease using the Cln7 KO mouse model. Experimental approaches
targeting the brain and the retina are currently tested for their safety and potential therapeutic efficacy.
In addition, small molecules are tested on Cln7 KO mice and their efficacy regarding the retardation of
neurodegeneration, neuroinflammation, disease progression and lysosomal storage are analyzed.
We have perfomed quantitative proteomics on Cln7 ko mouse embryonic fibroblasts (MEFs) to analyse
molecular mechanisms leading to lysosomal dysfunction in CLN7 disease. We found that 12 soluble
lysosomal proteins (blue circles) involved in the degradation of glycans, peptides, lipids and fatty acid-
modified proteins were significantly depleted in lysosomes in the absence of functional Cln7. In addition,
we observed a defect in the ability of Cln7 ko MEFs to adapt to starvation conditions as shown by impaired
mammalian target of rapamycin complex 1 reactivation, reduced autolysosome tubulation and increased
perinuclear accumulation of autolysosomes compared to controls.