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

Abstract

Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson’s disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM. Together, these data confirm that RAB39B controls AMPAR trafficking, which in turn plays a pivotal role in neuronal dendritic spine remodelling and that targeting Ca2+-permeable AMPARs may highlight future pharmaceutical interventions for RAB39B-associated disease conditions.

Loss of RAB39B does not alter MPTP-induced Parkinson’s disease-like phenotypes in mice

“…Interestingly, although the weight loss of Rab39b KO mice was more significant than that of WT mice after the first three injections of MPTP, the weight of Rab39b KO mice began to recover and returned to the level before MPTP treatment after the last injection. In previous studies, Rab39b KO mice showed some weight loss compared to littermate control WT at 2 months of age or throughout the early stage of growth (P7-P90), regardless of the mouse strains ( Niu et al, 2020 ; Mignogna et al, 2021 ). The loss of body weight in Rab39b KO mice could be attributed to a significant reduction in the volume of abdominal adipose tissue, whereas there were no significant differences in the weight of organs, food and water intake, body temperature, and glucose consumption in each brain region between genotypes ( Mignogna et al, 2021 ).…”

“…In previous studies, Rab39b KO mice showed some weight loss compared to littermate control WT at 2 months of age or throughout the early stage of growth (P7-P90), regardless of the mouse strains ( Niu et al, 2020 ; Mignogna et al, 2021 ). The loss of body weight in Rab39b KO mice could be attributed to a significant reduction in the volume of abdominal adipose tissue, whereas there were no significant differences in the weight of organs, food and water intake, body temperature, and glucose consumption in each brain region between genotypes ( Mignogna et al, 2021 ). Lack of activity caused by MPTP treatment translate into reduced food and water intake and a possible slight weight loss ( Jackson-Lewis and Przedborski, 2007 ).…”

Rab GTPases in Parkinson's disease: a primer

“…When expressed in various cell types, Rab39b localizes to the ER and Golgi complex [ 22 , 25 , 27 ], suggesting a role in anterograde secretory transport. Consistent with this notion, Rab39b and its downstream effector PICK1 (protein interacting with C-kinase 1) have been reported to regulate ER-Golgi trafficking and surface expression of the AMPA receptor (AMPAR) subunit GluA2 in hippocampal and cortical neurons [ 28 , 29 ]. The composition of AMPAR subunits determines its channel properties, and the loss of Rab39b skews AMPAR composition toward more calcium-permeable, GluA2-lacking forms.…”

“…The composition of AMPAR subunits determines its channel properties, and the loss of Rab39b skews AMPAR composition toward more calcium-permeable, GluA2-lacking forms. This alters synaptic activity and may contribute to the cognitive dysfunctions associated with Rab39b mutations [ 28 , 29 ]. It will be interesting to determine whether Rab39b, possibly in conjunction with PICK1, may regulate ER-Golgi trafficking and surface expression of receptors also in dopaminergic neurons.…”

Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

“…Mechanisms of GluA1 upregulation in the context of C9ORF72 RE has been associated with haploinsufficiency of C9ORF72 protein in lower motor neurons derived from patient iPSCs and C9ORF72 knockout mice (Shi et al, 2018) and also hippocampal neurons (Xiao et al, 2019). In support of this, the knockout of putative C9ORF72 interactor Rab39b in primary neuron culture results in increased GluA1 trafficking to dendrites (Mignogna et al, 2015(Mignogna et al, , 2021. Interestingly, despite early work indicating the low impact of NMDA receptor-mediated excitotoxicity on motor neurons, recent studies have shown an upregulation of the NMDA receptor subunit GluN1 (Shi et al, 2018) that can be rescued along with GluA1 upregulation using small molecule inhibitors of phosphatidylinositol-5-kinase signaling (Staats et al, 2019).…”