Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Abstract

Mucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1−/− cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0133-7) contains supplementary material, which is available to authorized users.

N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV

“…Mcoln1 −/− mice have been described previously to exhibit age-dependent cerebral and cerebellar microgliosis and astrogliosis (Grishchuk et al, 2014; Micsenyi et al, 2009), which is consistent with our CD68 stains in late-stage cerebellum (Fig. 2A, Fig.…”

“…The loss of mucolipin-1 and resulting defects in these and possibly other processes lead to a host of MLIV pathologies, including storage of cellular substrates like glycosphingolipids (GSLs) normally targeted to the lysosome for degradation, dysregulation of lysosomal pH, and the buildup of autophagosomes (Bach et al, 1975; Micsenyi et al, 2009; Venkatachalam et al, 2008; Venugopal et al, 2007; Wong et al, 2015; Ye et al, 2004). In addition, loss of mucolipin-1 secondarily leads to other abnormalities such as widespread gliosis, dysmyelination, and Purkinje cell abnormalities (Grishchuk et al, 2014; Micsenyi et al, 2009; Schiffmann et al, 2014) and death as further reported here. Numerous MLIV disease models have been generated that recapitulate cellular pathologies, including murine, Drosophila , and C. elegans models (Lima et al, 2012; Schaheen et al, 2006; Venkatachalam et al, 2008; Venugopal et al, 2007).…”

“…Based on previous findings of motor deficits in Mcoln1 −/− mice, we were particularly interested in the motor and exploratory activity of our cohort (Grishchuk et al, 2014). Many lysosomal diseases display motor phenotypes indicative of cerebellar abnormalities, such as diminished motor coordination, and there is evidence that miglustat can ameliorate these changes (Davidson et al, 2009; Zervas et al, 2001b).…”

“…Behavioral assessments were made at timepoints selected to represent pre-symptomatic (7–15 for open field/object placement, 15–16 wks for balance beam), early symptomatic (26 wks), and end-stage disease (32 wks) based on previous reports in Mcoln1 − / − mice (Grishchuk et al, 2014; Micsenyi et al, 2009; Venugopal et al, 2007). Mice were given a randomized number to blind the tester to genotype and treatment, and their tails color-coded per cage during testing to represent each blinded number.…”

“…Numerous MLIV disease models have been generated that recapitulate cellular pathologies, including murine, Drosophila , and C. elegans models (Lima et al, 2012; Schaheen et al, 2006; Venkatachalam et al, 2008; Venugopal et al, 2007). The MLIV mouse model (Mcoln1 − / − mice) displays progressive behavioral and locomotor deficits, including hind-limb clasping, abnormal gait, and cognitive impairment (Grishchuk et al, 2014; Venugopal et al, 2007). As the mechanism linking loss of mucolipin-1 to these abnormalities is not fully established, this knowledge gap yields a major obstacle to developing a direct therapy for this disorder.…”