Rabs, Membrane Dynamics, and Parkinson's Disease

Abstract

Genes encoding cellular membrane trafficking components, namely RAB7L1 and RAB39B, are more recently recognized factors associated with Parkinson's disease (PD). Encoded by a gene within the PARK16 locus, RAB7L1 interacts with Leucine-rich repeat kinase 2 (LRRK2) to act in intracellular transport processes that are likely important for neuronal survival and function. LRRK2 also directly phosphorylates a number of other Rab proteins. On the other hand, nonsense and missense mutations of the X-chromosome localized RAB39B were shown to underlie X-linked intellectual disability (ID) in male patients with early-onset PD. The cellular or neuronal functions of RAB39B are not yet known with certainty, but it has recently been shown to play a role in glutamate receptor trafficking. Importantly, RAB39B is also functionally connected to components for autophagy regulation, which affects α-synuclein processing and clearance. In this review, we discuss the association of Rabs with PD pathology, and potential etiological mechanisms whereby defects or deficiencies in certain Rab proteins could lead to PD susceptibility. J. Cell. Physiol. 232: 1626-1633, 2017. © 2016 Wiley Periodicals, Inc.

Rab GTPases and Membrane Trafficking in Neurodegeneration

“…About 95% of PD cases are sporadic and the rest is familial. To date, mutations in at least 18 genes have been ‘associated’ with the etiology of PD, and a few of these mutations have been implicated in Rab function and membrane trafficking: Rab39B, α-synuclein (SNCA), PTEN-induced putative kinase 1 (PINK1) and leucine-rich repeat kinase 2 (LRRK2) [ 131 , 132 ].…”

“…Rab39B is exclusively expressed in neurons, localizes to the Golgi, and functions in trafficking of AMPA receptor subunit GluA2 to postsynaptic membrane in hippocampal neurons ( Figure 1 ). Rab39B mutant neurons show increased levels of immature GluA2, which leads to the formation of AMPA receptors lacking this subunit and has been associated with immature synapses and intellectual disability [ 74 , 132 ]. This is a direct demonstration of how a defective Rab GTPase can underlie neurodegeneration (class A, Figure 2 ; Table 1 ), although the exact mechanism of how Rab39B loss-of-function leads to selective neurodegeneration in dopaminergic neurons remains elusive [ 25 , 132 ].…”

Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis

“…First, LRRK2 translocates to membranes following Toll-like receptor stimulation of immune cells ( Schapansky et al, 2014 ). Second, LRRK2 is reported to regulate the autophagosome/lysosome system, which is particularly interesting as defects in proteins coordinating this pathway are found in multiple forms of PD ( Beilina and Cookson, 2016 ; Giaime et al, 2017 ; Tang, 2017 ). Third, LRRK2 phosphorylates at least three Rab GTPases (Rab8A, Rab10 and Rab12) in cultured human and murine cells as well as in mice, and this reduces their binding affinity for different Rab regulatory proteins ( Ito et al, 2016 ; Steger et al, 2016 ; Thirstrup et al, 2017 ).…”

The emerging role of Rab GTPases in the pathogenesis of Parkinson's disease

“…In contrast, the overexpression of WT Rab7L1 in WT primary mouse cortical cultures caused neurite shortening, perhaps as a result of the dysregulation of the stoichiometric ratio of components of the LRRK2 complex that are required for normal LRRK2 function . In humans, the interaction of variants at additional genetic loci that can influence PD susceptibility may explain why Rab7L1 has been associated with both elevated and reduced risk of PD . In a C. elegans model, the protein complex 3, a known regulator of endosome to lysosome trafficking, was shown to be a downstream effector of LRRK2 and RAB7L1.…”