Recent studies of ovine neuronal ceroid lipofuscinoses from BARN, the Batten Animal Research Network

Abstract

Studies on naturally occurring New Zealand and Australian ovine models of the neuronal ceroid-lipofuscinoses (Batten disease, NCLs) have greatly aided our understanding of these diseases. Close collaborations between the New Zealand groups at Lincoln University and the University of Otago, Dunedin, and a group at the University of Sydney, Australia, led to the formation of BARN, the Batten Animal Research Network. This review focusses on presentations at the 14th International Conference on Neuronal Ceroid Lipofuscinoses (Batten Disease), recent relevant background work, and previews of work in preparation for publication. Themes include CLN5 and CLN6 neuronal cell culture studies, studies on tissues from affected and control animals and whole animal in vivo studies. Topics include the effect of a CLN6 mutation on endoplasmic reticulum proteins, lysosomal function and the interactions of CLN6 with other lysosomal activities and trafficking, scoping gene-based therapies, a molecular dissection of neuroinflammation, identification of differentially expressed genes in brain tissue, an attempted therapy with an anti-inflammatory drug in vivo and work towards gene therapy in ovine models of the NCLs. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

“…The major neuropathological features of CLN5 Batten sheep closely mirror those of human CLN5 Batten disease (a variant late-infantile Batten disease) caused by mutations in the human CLN5 gene (Jolly et al 2002;Frugier et al 2008;Palmer et al 2015;Perentos et al 2015). As with many other forms of Batten disease, mutations in the CLN5 gene have been shown to trigger early synaptic pathology in the affected brain regions of mouse models (von Schantz et al 2009).…”

“…CLN5 sheep and heterozygous controls were born, raised, and diagnosed from a flock of Borderdale sheep at Lincoln University (New Zealand) (Frugier et al 2008;Palmer et al 2015). Heterozygous sheep were chosen as controls because they do not develop any signs of disease (based on clinical and postmortem observations of over a hundred breeding ewes kept for an average of seven years) but otherwise share their genetic background with the homozygous sheep.…”

“…2008; Palmer et al. 2015). This mutation leads to the loss of a 5′ splice donor site between exon and intron 3, resulting in excision of exon 3, a downstream frame shift and premature termination of translation.…”

“…The sheep used in this study have a late infantile variant CLN5 form of Batten disease. A number of naturally occurring large animal forms of CLN5 Batten disease have been described, including two in dogs (Melville et al 2005;Gilliam et al 2015), a form in cattle (Houweling et al 2006), and this well-developed form in New Zealand Borderdale sheep, which have a c.571 + 1G>A splice site mutation in the CLN5 gene that causes disease (Jolly et al 2002;Frugier et al 2008;Palmer et al 2015).This mutation leads to the loss of a 5 0 splice donor site between exon and intron 3, resulting in excision of exon 3, a downstream frame shift and premature termination of translation.…”

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for aCLN5Nonsense Mutation Previously Identified in Border Collies

“…[44][45][46] The ovine model is involved with ongoing and planned experiments to evaluate potential therapies for human CLN5 patients. 47 Several canine models have been used to develop therapies for lysosomal storage diseases, 48 and dogs have obvious advantages over sheep in urban research settings. A TPP1-deficient canine NCL model 5 has proven useful in the evaluation of therapies for the human CLN2 form of NCL including an enzyme replacement therapy that is currently in clinical trials in human patients (https://clinicaltrials.gov/ct2/show/NCT0 1907087).…”