Abstract
RAB39B is located on the X chromosome and encodes the RAB39B protein that belongs to the RAB family. Mutations in RAB39B are known to be associated with X-linked intellectual disability (XLID), Parkinson’s disease, and autism. However, the patho/physiological functions of RAB39B remain largely unknown. In the present study, we established Rab39b knockout (KO) mice, which exhibited overall normal birth rate and morphologies as wild type mice. However, Rab39b deficiency led to reduced anxiety and impaired learning and memory in 2 months old mice. Deletion of Rab39b resulted in impairments of synaptic structures and functions, with reductions in NMDA receptors in the postsynaptic density (PSD). RAB39B deficiency also compromised autophagic flux at basal level, which could be overridden by rapamycin-induced autophagy activation. Further, treatment with rapamycin partially rescued impaired memory and synaptic plasticity in Rab39b KO mice, without affecting the PSD distribution of NMDA receptors. Together, these results suggest that RAB39B plays an important role in regulating both autophagy and synapse formation, and that targeting autophagy may have potential for treating XLID caused by RAB39B loss-of-function mutations.
Highlights
Intellectual disability (ID) refers to a group of neurodevelopmental disorders characterized by severe defects in both cognition and adaptive behavior, which start before the age of 18 years (Vissers et al, 2016; Iwase et al, 2017)
We confirmed that RAB39B was expressed in the brain but not other tissues detected in 2 months old C57BL/6J mice (Supplementary Figure 1A)
Levels of Iba1 and GFAP in these brain regions were comparable between 2 months old wild type (WT) and Rab39b KO mice (Supplementary Figures 5B, 8A), suggesting that loss of Rab39b has no effect on glial activation at this age
Summary
Intellectual disability (ID) refers to a group of neurodevelopmental disorders characterized by severe defects in both cognition (with an IQ score of less than 70) and adaptive behavior, which start before the age of 18 years (Vissers et al, 2016; Iwase et al, 2017) Environmental factors such as maternal drug abuse during pregnancy and birth complications can cause ID, increasing evidence indicates that genetics plays a significant role in the pathogenesis of ID (Vissers et al, 2016; Iwase et al, 2017). Genomic/genetic variants in more than 100 genes on X chromosome have been associated with XLID (Peng et al, 2017). Detailed molecular pathways underlying ID pathogenesis driven by each of these genes remain largely unknown; and elucidation of underlying molecular mechanisms shall provide new insights into disease therapeutic strategies
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