Tracking sex-dependent differences in a mouse model of CLN6-Batten disease

Abstract

BackgroundCLN6-Batten disease is a rare neurodevelopmental disorder characterized pathologically by the accumulation of lysosomal storage material, glial activation and neurodegeneration, and phenotypically by loss of vision, motor coordination, and cognitive ability, with premature death occurring in the second decade of life. In this study, we investigate whether sex differences in a mouse model of CLN6-Batten disease impact disease onset and progression.ResultsA number of noteworthy differences were observed including elevated accumulation of mitochondrial ATP synthase subunit C in the thalamus and cortex of female Cln6 mutant mice at 2 months of age. Moreover, female mutant mice showed more severe behavioral deficits. Beginning at 9 months of age, female mice demonstrated learning and memory deficits and suffered a more severe decline in motor coordination. Further, compared to their male counterparts, female animals succumbed to the disease at a slightly younger age, indicating an accelerated disease progression. Conversely, males showed a marked increase in microglial activation at 6 months of age in the cortex relative to females.ConclusionsThus, as female Cln6 mutant mice exhibit cellular and behavioral deficits that precede similar pathologies in male mutant mice, our findings suggest the need for consideration of sex-based differences in CLN6 disease progression during development of preclinical and clinical studies.Electronic supplementary materialThe online version of this article (10.1186/s13023-019-0994-8) contains supplementary material, which is available to authorized users.

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures

“…This is consistent with previous findings in CLN3 disease patients (juvenile Batten disease) where females typically display a more severe trajectory of symptoms compared to males 33 . Our findings also align with research in the CLN6 (variant late infantile NCL) mouse in that onset of some behavioral signs were earlier and more severe in females compared to males 34 , 35 . Although it is tempting to extrapolate findings between various forms of CLN disease, this should be viewed cautiously since these diseases can have fundamentally different causes.…”

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures

“…This is consistent with previous findings in CLN3 disease patients (juvenile Batten disease) where females typically display a more severe trajectory of symptoms compared to males 33 . Our findings also align with research in the CLN6 (variant late infantile NCL) mouse in that onset of some behavioral symptoms were earlier and more severe in females compared to males 34,35 . Although it is tempting to extrapolate findings between various forms of CLN disease, this should be viewed cautiously since these diseases can have fundamentally different causes.…”

Sex-split analysis of pathology and motor-behavioral outcomes in a mouse model of CLN8-Batten disease reveals an increased disease burden and trajectory in female Cln8mnd mice

“…Previous investigations of neural injuries in mice offer support for an association between enhanced gliotic activity and poorer motor-behavioral outcomes in assessments like the MWM [ 42 – 44 ]. However, it is worth noting that prior investigation of sex differences of a CLN6 disease mouse model revealed Cln6 nclf males experience greater microgliosis than Cln6 nclf females at 6 months of age within the S1BF despite Cln6 nclf females perishing earlier and exhibiting poorer motor-behavioral outcomes [ 31 ]. These differences in pathological variations, such as increases in male ASM versus female SubC and increases in female gliosis in one NCL model versus male gliosis in another, highlight the complexity of interpreting pathological changes and their relation to disease progression and treatment outcomes, and specifically suggest that a more holistic approach may be required for this purpose.…”

“…For instance, sex-dependent differences in gene expression response to galactosylceramide were found in the Cln3 Δex7/8 murine model [ 30 ]. Further, Poppens et al described female Cln6 nclf mice to experience accelerated disease progression, more severe behavioral issues and motor decline, and differences in histopathological effects [ 31 ]. A prior investigation of Cln8 mnd mice revealed sex differences in retinal vulnerability where female retinas exhibited higher oxidation rates and caspase-3 mediated apoptosis, in addition to a more severe histopathological profile of the retina [ 32 ].…”