RAB39B Deficiency Impairs Learning and Memory Partially Through Compromising Autophagy

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.

RAB39B-mediated trafficking of the GluA2-AMPAR subunit controls dendritic spine maturation and intellectual disability-related behaviour

“…Zang et al [38] reported that Rab39b KO mice had cortical neurogenesis deficits, macrocephaly, and social and motor deficits. Similar behavioural performance was observed by Niu et al [39], demonstrating short-term working memory deficits, but the authors did not observe macrocephaly in agreement with our results. As suggested [39], this discrepancy may be caused by defects in metabolic or different biological processes between different genetic backgrounds (C57Bl/6J vs C57Bl/6N) or by the mouse age analysed.…”

“…Concerning cognitive functions, Rab39b KO mice showed a slight deficit in the radial maze working memory task, which was also reported by Niu et al with different learning paradigms [39] and a drastic impairment in trace fear conditioning.…”

Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

“…[Color figure can be viewed at wileyonlinelibrary.com] gene expression in mouse N2A cells a reduction in autophagolysosome formation has been observed, suggesting decreased autophagic flux. 124 When autophagy was induced with rapamycin, this impairment was eliminated, indicating that a loss of RAB39B expression impairs basal autophagy, but not autophagy induction. Notably, rapamycin treatment improved defects in synaptic plasticity and memory observed in RAB39B gene knockout mice, suggesting that autophagy plays a central role in phenotypes observed with RAB39B deficiency.…”

“…123 Despite the findings of these in vitro-based investigations, a recent study of RAB39B gene knockout mice has observed a reduction of postsynaptic NMDA receptor subunits as oppose to AMPA receptors, suggesting that in vivo deficits in synaptic function may differ from those established within in vitro models. 124…”

“…Although the mechanisms by which a loss of RAB39B leads to the dyshomeostasis of aSyn is unknown, the disruption of autophagic clearance has recently been proposed as central to this, in line with the impairments seen following the expression of mutations within the RAB39B GEF C9orf72 128 and would appear to be supported by the autophagy deficits in RAB39B knockout mice. 124 Whilst such a proposition is interesting it remains unclear why such generalized failure of lysosomal clearance would preferentially lead to the accumulation and aggregation of aSyn over other aggregate prone proteins, and indeed several studies have failed to find an impact upon lysosomal degradation following the loss of RAB39B. 126,127 Equally, it must also be considered that Lewy pathology is not commonly reported in cases of amyotrophic lateral sclerosis and frontotemporal disease associated with the loss of function hexanucleotide repeat expansion of the c9orf72 gene 129 and thus such a close relationship between the mode of cellular dysfunction induced by a loss of RAB39B activity and the loss of c9orf72 activity would seem unlikely.…”