RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies

Abstract

Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X‐linked Parkinson’s disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha‐Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post‐mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer’s disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co‐localized with beta‐amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B‐associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co‐aggregation of RAB39B with Aβ in plaques suggests that age‐associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases.

Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

“…2B). This secondary consequence of vesicular aggregation formation is consistent with our previous observation of sequestration of RAB11a and RAB13 in cellular models of aSyn deposition as well as the coaggregation of RAB39B in a subpopulation of LBs in idiopathic DLB cases, 109 which together implicate the dysfunction of key RAB proteins for both familial cases of LBD and idiopathic variants. Furthermore, should a loss of functional RAB39B be mediated by its inclusion within LBs, affected neurons maybe further impacted by downstream alterations of synaptic homeostasis as a consequence of altered glutamatergic signalling and autophagic deficits.…”

“…For example, whilst current studies focused on the health of individual cells would appear to support a protective role for RAB39Bmediated trafficking in the clearance of intracellular aSyn, caution must be exercised, as if RAB39B functions serve to facilitate the extracellular release of aSyn as opposed to its ultimate degradation, its further activation may augment prion-like spread of pathology and thus be detrimental in the context of the whole brain as opposed to that of a single cell. Despite the low frequency of RAB39B mutations within the human population and the confounding XLID presentation of carriers, the recent observations made by ourselves and others of a disruption of RAB39B subcellular distribution and also of its sequestration in LBs in idiopathic cases of LBD, 97,109 further strengthens the need to clarify the relationship between RAB39B and aSyn and indeed its role in the formation of concomitant diseasemodifying pathologies.…”

“…Indeed, ourselves and others have recently reported on the loss and/or redistribution of RAB39B in idiopathatic LBD variants. 97,109…”

Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

“…In those limited cases where α-synuclein immunoreactivity has been investigated, both subcortical and cortical LBs were reported [36,133]. Furthermore, we have recently reported RAB39B as reduced in post-mortem LBD brain tissue and sequestered into some LBs, potentially indicating a role for RAB39B in idiopathic LBD [67]. To the best of our knowledge, α-synuclein aggregation has not yet been investigated in RAB39B rodent models.…”

The Role of Rab Proteins in Parkinson’s Disease Synaptopathy

“…In some cases, these forms do not present LB or LN, and the incurring disease is defined as parkinsonism in that, neuropathologically, PD is defined by the presence of LB. Some of the genes mutated in PD encode for proteins involved in synaptic functions, such as: Ras-associated binding protein 39b (Rab39b), synaptojanin 1 (SYNJ1), Leucine-rich repeat kinase 2 (LRRK2), synphilin-1 (SYPH1) and transmembrane protein 230 (TMEM230) [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. On the other hand, several PD-associated genes, including those encoding for some of the aforementioned proteins (RAB39B, SYPH1, SYNJ1 and TMEM230, in addition to GBA1, Parkin, PINK-1, ATP13A2, FBXO7 and SYT11), have been linked to dysregulations of ALP [ 31 , 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”