Longitudinal characterization of the Cln8^mnd mouse model of CLN8 Batten Disease.

Abstract

Purpose : Northern epilepsy (CLN8) is the most common disease of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders, Batten disease. The NCL disorders affect the nervous system and produce alterations on visual, motor and cognitive skills. CLN8 is caused by mutations on the CLN8 gene coding for a transmembrane protein localized on the endoplasmic reticulum (https://ghr.nlm.nih.gov/condition/cln8-disease).

The naturally occurring motor neuron degeneration mouse (B6.KB2-Cln8mnd/MsrJ) presents a mutation in the Cln8 gene and it has been shown to be a model for CLN8 (Ranta and Lehesjoki 2000). This mouse strain is characterized by lipofuscin accumulation, motor dysfunction, retinal degeneration and mitochondrial degeneration (Messer et al. 1993; Cooper et al. 1999). We have characterized the Cln8^mnd mouse model between two and eight months of age.

Methods : Kinematic gait analysis, T2 volumetry and DTI for white matter evaluation, 1H-MRS and FDG-PET metabolic profiling, and flash ERG data from both genders was collected at two, four, six and eight months of age.

Results : The male Cln8^mnd mice showed significantly decreased whole brain volumes already by two months of age (98%, p < 0.01). Moreover, there is a clear appearance of demyelinated brain regions already at two months of age for both genders. The neurometabolic profile presented significant alterations starting at four months of age for the males (GPC, p = 0.005 and GSH, p = 0.034), and at six months of age for the females (Ala, p = 0.024 and TAU, p = 0.016). The functionality of the visual system appeared hindered by four months of age, with significant lower a-wave (3 cd.s/m2, 55%, p = 0.0001; 10 cd.s/m2, 53%, p < 0.0001) and B-wave amplitudes (3 cd.s/m2, 70%, p < 0.0001; 10 cd.s/m2, 69%, p < 0.0001). By eight months of age the mutant mice showed no response to fERG. Movement started to show significant impairment already by two months of age in both genders and worsen at six months (gait score, 81%, p < 0.01 and 0.001, respectively).

Conclusions : The Cln8^mnd mouse strain showed significant differences in many of the parameters analyzed already at two months of age, brain volume, neurometabolic profile, visual function and movement. Upon aging the mutant mice phenotype worsened in all the parameters.

This is a 2020 ARVO Annual Meeting abstract.