Mole Laboratory: Juvenile Batten Disease

Sara Mole, Michael Bond, Mariana Vieira, Davide Marotta, Sophia kleine Holthaus, Rachel Brown MRC Laboratory for Molecular Cell Biology, University College London, London, UK, WC1E 6BT, s.mole@ucl.ac.uk

INTRODUCTION and OBJECTIVES Ñ Juvenile CLN3 disease, or JNCL, is caused by a 1 kb deletion within the CLN3 gene. Other mutations can affect age of onset, and disease progression and severity. The exact function of CLN3 is not known.

Ñ  It is important to know what CLN3 does, how it does this, and what goes wrong in disease, so that new therapies can be designed.

Ñ  Our laboratory is working to achieve this by simplifying the system used to answer the questions or identify new drug targets or develop therapeutic approaches, before applying to more complex human cells and animal models.

Ñ We are also identifying the challenges to developing therapy for CLN3 disease, beginning with the loss of vision.

KEY PROJECTS WHAT THIS MEANS FOR THERAPY

Developing gene therapy for the loss of vision using mouse models

Studying the effect of different mutations in CLN3, first in yeast and

then in human cells Studying what CLN3 does and where it does it, in a single cell organism such as

yeast (where it is called btn1)

Identify new drugs and new targets for therapy in yeast strains with different CLN3 mutations, using

multiple approaches Acknowledgements: Many scientists and families

Vacuole size Cytokinesis delay/septation

Monopolar growth, 7 h 37ºC Cell curving (MT), 4 h 37ºC

THERAPY

1.  We are simplifying learning what CLN3 does

2.  We are identifying new genes or drugs that rescue CLN3 disease in yeast

3.  We extrapolate these results to patients cells and then to fish and mouse models

4.  We use this knowledge to transfer or design and then test new and better therapeutic approaches

5.  We use approaches that

work, such as gene therapy for visual failure

6.  We apply this to CLN3 disease

7.  We are learning what challenges need to be overcome

8.  Retaining or restoring sight will significantly improve the quality of life for patients and their families

RESCUE

Function

Therapy

Mutations

Disease

Genes Models

Btn1%

Vacuolar%%morphology%/%pH%

Btn1%

Trafficking%%

Cell%polarity%Cell%wall%

Osmoregula=on%Heat%tolerance% Septa=on%

Metabolic%perturba=on%

Golgi%size,%number,%shape,%

and%structure%%

GA#

VAC#

MIT#

Glycerol Glucose

wt

btn1Δ

btn1Δ wt Mito

chon

dria

l mem

bran

e po

tent

ial (

arbi

trary

uni

ts)

Glucose Glycerol

Glucose Glycerol btn1Δ

wt

Via

bilit

y (%

)

Time (hours)

wt with glycerol wt with glucose

btn1Δ with glycerol btn1Δ with glucose

btn1Δ

wt

btn1Δ

200nm

wt

Mutation: E295K

1kb deletion

1 Kb deletion

Function/therapy targets

cDNA library

Transposon mutagenesis

Small molecule/

drug

NCL Resource – A gateway for Batten disease www.ucl.ac.uk/ncl