Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

Abstract

Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators.

The Role of Rab Proteins in Parkinson’s Disease Synaptopathy

“…Moreover, the study reported the presence of axonal spheroids, structures reminiscent of the Wallerian-like degeneration observed in neurodegenerative diseases with impaired axonal transport [ 93 ], in the white matter tracts of the basal ganglia of the post-mortem brain of a patient bearing the c.503C > A RAB39B mutation [ 92 ]. This is in agreement with the involvement of Rab39b in endocytic retrograde and/or early-stage anterograde secretory transport [ 32 ].…”

“…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 ].…”

Rab GTPases in Parkinson's disease: a primer

“…The most compelling evidence for the deregulation of Rab proteins as a primary cause of PD comes from studies of Rab39b [20,21]. Mutations in Rab39b cause X-linked intellectual disability associated with autism, epilepsy and macrocephaly, as well as rare early-onset PD with classical clinical symptoms, Lewy body pathology and dopaminergic cell loss in the substantia nigra [22][23][24].…”

“…Mutations in Rab39b cause X-linked intellectual disability associated with autism, epilepsy and macrocephaly, as well as rare early-onset PD with classical clinical symptoms, Lewy body pathology and dopaminergic cell loss in the substantia nigra [22][23][24]. Atypical PD-causing mutations in Rab39b generally result in the loss of protein expression [20,21]. Rab39b is enriched in the brain, and in situ hybridization studies indicate that expression may be neuron-specific [25].…”

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease

“…This is the case for Rab39B, which is involved in α-syn homeostasis, endosomal traffic, neurite outgrowth, synaptic maturation, and autophagy [ 50 ]. Rab39B mutation causes a rare form of early-onset PD with an α-syn pathology [ 68 ].…”