Maternal immune activation modifies the course of Niemann-pick disease, type C1 in a gender specific manner

Abstract

Niemann-Pick disease, type C1 (NPC1) is a rare neurodegenerative lysosomal storage disease with a wide spectrum of clinical manifestation. Multiple genetic factors influence the NPC1 mouse phenotype, but very little attention has been given to prenatal environmental factors that might have long-term effects on the neuroinflammatory component of NPC1 pathology. Studies in other mouse models of cerebellar ataxia have shown that developmental exposures lead to Purkinje neuron degeneration later in life, suggesting that environmental exposures during development can impact cerebellar biology. Thus, we evaluated the potential effect of maternal immune activation (MIA) on disease progression in an Npc1 mouse model. The MIA paradigm used mimics viral infection using the toll like receptor 3 agonist polyinosinic-polycytidilic acid during gestation. Through phenotypic and pathologic tests, we measured motor and behavioral changes as well as cerebellar neuroinflammation and neurodegeneration. We observed a gender and genotype dependent effect of MIA on the cerebellum. While the effects of MIA have been previously shown to primarily affect male progeny, we observed increased sensitivity of female mutant progeny to prenatal exposure to treatment with polyinosinic-polycytidilic acid. Specifically, prenatal MIA resulted in female NPC1 mutant progeny with greater motor deficits and a corresponding decrease in cerebellar Purkinje neurons. Our data suggest that prenatal environmental exposures may be one factor contributing to the phenotypic variability observed in individuals with NPC1.

Evaluation of the Potential Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Niemann–Pick Disease, Type C1

“…No obvious differences were seen between the Pcsk9 +/+ and Pcsk9 +/mice and these data were combined as Pcsk9 ctrl . Single knockout Npc1 -/-/Pcsk9 ctrl male (n = 10) and female (n = 14) mice had an initial normal, but slightly reduced, weight-gain followed by weight loss starting at about 6-7 weeks of age as expected for the Npc1 -/phenotype [44,45]. In the double knockout Npc1 -/-/Pcsk9 -/mice, both male (n = 6) and female (n = 7) mice were similar to the Npc1 -/-/Pcsk9 ctrl mice, showing a similar weight loss pattern consistent with the phenotype of Npc1 -/mutant mice alone ( Figure 1A,B).…”

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine

“…For example, Bianconi’s group 131 showed that female Npc1 mutant mice (BALB/c npc nih ) live significantly longer (median survival of 78 days) than male Npc1 mice (median survival of 66 days). In 2020, Cougnoux’s group 132 reported similar data on the C57BL/6J background. The mean survival was 65 ± 7 days and 55 ± 16 for C57BL/6J female and male mutant mice, respectively.…”

“…The average survival previously reported for these mice ranges between 70 and 90 days 135 . On top of this, Cougnoux and colleagues 132 reported that in their facility, the Npc1 nih/nih mice in the C57BL/6J genetic background lived 61 ± 12 days and had a predominantly neurological phenotype with loss of cerebellar Purkinje neurons in C57BL/6J Npc1 nih/nih mice, like that observed in Npc1 nih/nih BALB/c mice. However, as mentioned above, Parra and colleagues have reported that these mice lived 32 days 71 and had a predominantly visceral phenotype.…”

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

“…Numerous double mutant mice have been created to test whether and how specific candidate genes impact the disease [163,173,177,190,191,[219][220][221][222][223][224][225][226][227][228][229][230][231][232][233][234][235]. Sex-dependent differences in behavior [236], life span [37,134], and responses to immune activation [237] and to potential therapies [171,238] were reported in some NPC1 mutant mice, raising the question of whether sex is a modifying factor in NPC disease [37] as in other cholesterol-related pathologies [239][240][241][242] and normal cholesterol homeostasis [243,244].…”