RAB39B's role in membrane traffic, autophagy, and associated neuropathology

Abstract

Neuropathological disorders are increasingly associated with dysfunctions in neuronal membrane traffic and autophagy, with defects among members of the Rab family of small GTPases implicated. Mutations in the human Xq28 localized gene RAB39B have been associated with X-linked neurodevelopmental defects including macrocephaly, intellectual disability, autism spectrum disorder (ASD), as well as rare cases of early-onset Parkinson's disease (PD). Despite the finding that RAB39B regulates GluA2 trafficking and could thus influence synaptic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor subunit composition, reasons for the wide-ranging neuropathological consequences associated with RAB39B defects have been unclear. Recent studies have now unraveled possible mechanisms underlying the neuropathological roles of this brain-enriched small GTPase. Studies in RAB39B knockout mice showed that RAB39B interacts with components of Class I phosphatidylinositol-3-kinase (PI3K) signaling. In its absence, the PI3K-AKTmechanistic target of rapamycin signaling pathway in neural progenitor cells (NPCs) is hyperactivated, which promotes NPC proliferation, leading to macrocephaly and ASD. Pertaining to early-onset PD, a complex of C9orf72, Smith-Magenis syndrome chromosome region candidate 8 and WD repeat domain 41 that functions in autophagy has been identified as a guanine nucleotide exchange factor of RAB39B. Here, recent findings that have shed light on our mechanistic understanding of RAB39B's role in neurodevelopmental and neurodegenerative pathologies are reviewed. Caveats and unanswered questions are also discussed, and future perspectives outlined.

Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

“…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.…”

Personalized Perturbation Profiles Reveal Concordance between Autism Blood Transcriptome Datasets

“…C19orf53 correlates with PARK7, SOD1 and ROCK1 which have roles in autophagic proteolysis and the formation of the autophagosome [53][54][55] . Our correlation analysis also reveals C1orf109 is highly correlated with TMEM41B, ATG4C RAB39B, TRIM8, and NPRL3 which are also regulators of autophagy [56][57][58][59] . C1orf109 was shown here to be highly correlated with SNCA.…”

Psychosis in Parkinson’s Disease: A Lesson from Genetics

“…More recently, additional evidence reported that loss-of-function mutations in RAB39B , including whole gene deletion, missense, splicing and frameshift variants, also led to the development of an X-linked form of rare early-onset PD associated with intellectual disability [ 72 , 73 ]. RAB39B is a neuronal protein which is localized in the Golgi compartment and acts as an essential regulator of vesicular trafficking, possibly affecting α-syn homeostasis [ 74 ]. This protein is also believed to play a role in the modulation of growth cone function, neurite morphology, synaptic plasticity and synapse formation [ 74 , 75 ].…”