Trafficking cellular proteins in childhood brain diseases

Sheep neurons (red) expressing green fluroescent protein (green) delivered by a gene therapy vector.
Sheep neurons (red) expressing green fluroescent protein (green) delivered by a gene therapy vector.
Dr Stephanie Hughes from the Department of Biochemistry was recently awarded $14,400 to study the use of gene therapy in a childhood neurodegenerative disease.

Batten disease, or neuronal ceroid lipofuscinoses (NCL), is a group of monogenic lysosomal storage disorders characterised by childhood blindness, seizures, dementia, progressive decline to a vegetative state and premature death.

Ten distinct genetic loci have been identified to date with mutations in genes encoding either soluble lysosomal proteins or transmembrane proteins resident in either the lysosome or the endoplasmic reticulum.

We have extensively studied two forms of these disorders in sheep, however only recently have mutations been identified in the sheep.

One of the sheep forms has a mutation in a gene encoding the soluble lysosomal protein, CLN5.

The protein has no significant homology to any other protein, nor has the function of either been established.

These sheep provide a unique resource for both studies of protein biology and for pre-clinical testing of therapeutic strategies.

Here, we aim to test the effects of CLN5 mutations on protein trafficking to the lysosome and endoplasmic reticulum.

In addition the correct trafficking of wildtype CLN5 proteins in mutant sheep neurons and the effects of gene replacement on function of affected neurons will be tested.

These studies will provide important information on protein trafficking and the potential for functional gene correction in Batten disease.

This work forms part of a collaboration with Dr Hughes's and her lab members Katie Hope and Nicole Neverman and Professor David Palmer's group at Lincoln University.

 

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