(application abstract): The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited pediatric neurodegenerative diseases.
The aim of this application is to exploit neuron cultures developed from an ovine model as an in vitro model of human disease and use it, in combination with whole animal studies, to study the mechanism of neurodegeneration and explore possible therapies. The NCLs are characterized by profound neurodegeneration and the intracellular accumulation of subunit c of mitochondrial ATP synthase. Cortical neuronal cultures have been established from affected sheep and storage body accumulation observed in cultured cells. This investigation will optimize these neuron Cultures as a model of the in situ pathology. The mechanism of neurodegeneration will be studied in them. Specific hypotheses to be tested are that subunit c storage is directly related to neurodegeneration, that a disruption in the endosome-lysosome pathway is central to the neurodegeneration and that accumulation of subunit c results in over-activity of an oligomeric subunit c ionpore in the neuronal plasma membrane. The role of apoptosis and excitotoxicity will be examined and the efficacy of IGF1 and other growth factors that might overcome neurodegeneration tested. Chimeric normal/affected sheep will be generated to delineate the possibilities for gene and enzyme therapy. The clinical course of disease will be monitored in affected sheep transgenically overexpressing IGF1 in brain, to determine if this ameliorates the development of symptoms. Possible therapies will be tested in whole animal experiments. Results will be relevant to understanding the pathobiology of the NCLs and will test the likelihood of benefits of possible treatments. Findings will also be relevant to understanding other protein storing neurodegenerative diseases, such as Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21NS040297-01S1
Application #
6448833
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Spinella, Giovanna M
Project Start
2000-09-08
Project End
2003-08-31
Budget Start
2000-09-08
Budget End
2001-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$16,000
Indirect Cost
Name
Lincoln University
Department
Type
DUNS #
592214472
City
Canterbury
State
Country
New Zealand
Zip Code
8000
Sawiak, Stephen J; Perumal, Sunthara Rajan; Rudiger, Skye R et al. (2015) Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging. PLoS One 10:e0132331
Cooper, Jonathan D (2010) The neuronal ceroid lipofuscinoses: the same, but different? Biochem Soc Trans 38:1448-52
Wong, Andrew M S; Rahim, Ahad A; Waddington, Simon N et al. (2010) Current therapies for the soluble lysosomal forms of neuronal ceroid lipofuscinosis. Biochem Soc Trans 38:1484-8
Frugier, Tony; Mitchell, Nadia L; Tammen, Imke et al. (2008) A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571+1G>A) leading to excision of exon 3. Neurobiol Dis 29:306-15
Kay, Graham W; Oswald, Manfred J; Palmer, David N (2006) The development and characterisation of complex ovine neuron cultures from fresh and frozen foetal neurons. J Neurosci Methods 155:98-108