Rab GTPases and Membrane Trafficking in Neurodegeneration

Abstract

Defects in membrane trafficking are hallmarks of neurodegeneration. Rab GTPases are key regulators of membrane trafficking. Alterations of Rab GTPases, or the membrane compartments they regulate, are associated with virtually all neuronal activities in health and disease. The observation that many Rab GTPases are associated with neurodegeneration has proven a challenge in the quest for cause and effect. Neurodegeneration can be a direct consequence of a defect in membrane trafficking. Alternatively, changes in membrane trafficking may be secondary consequences or cellular responses. The secondary consequences and cellular responses, in turn, may protect, represent inconsequential correlates or function as drivers of pathology. Here, we attempt to disentangle the different roles of membrane trafficking in neurodegeneration by focusing on selected associations with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and selected neuropathies. We provide an overview of current knowledge on Rab GTPase functions in neurons and review the associations of Rab GTPases with neurodegeneration with respect to the following classifications: primary cause, secondary cause driving pathology or secondary correlate. This analysis is devised to aid the interpretation of frequently observed membrane trafficking defects in neurodegeneration and facilitate the identification of true causes of pathology.

Sequence-dependent trafficking of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

“…Given the present findings, however, GDE2 dysfunction could result from impaired endocytic trafficking rather than from loss-of-function mutations. Importantly, impaired trafficking is a hallmark of human neurodegenerative disease, including amyotrophic lateral sclerosis (ALS), Parkinson's and Alzheimer's disease (De Vos and Hafezparast, 2017;Kiral et al, 2018;McMillan et al, 2017;Schreij et al, 2016;Xu et al, 2018).…”

Microglia roles in synaptic plasticity and myelination in homeostatic conditions and neurodevelopmental disorders

“…Microglia are also involved in myelin debris clearance in normal aging (Shobin et al, 2017) and in disease conditions, as shown in cuprizone-induced demyelination models (Poliani et al, 2015;Skripuletz et al, 2010). The importance of myelin debris clearance by microglia was demonstrated by blocking microglia-specific phagocytosis through inhibition of Rab7 (a key regulator in endolysosomal trafficking (Kiral, Kohrs, Jin, & Hiesinger, 2018)). This manipulation resulted in enhanced accumulation of myelin fragments in microglial endosomes and prevented remyelination (Safaiyan et al, 2016), emphasizing the microglia's key role in synaptic plasticity.…”

Neurodegeneration caused by LRRK2-G2019S requires Rab10 in select dopaminergic neurons

“…Here, we use a Drosophila model to address the link from LRRK2 Rabs are a plausible LRRK2 substrate leading to neurodegeneration, as they act as molecular switches interacting with a range of proteins (GEFs, GAPs and GDIs) regulating supply and delivery of cargo to membranes. Indeed many of the 66 Rabs in humans have been linked to neurodegenerative disorders (9). Mutations in Rabs 29 and 39 cause Parkinson's (10)(11)(12).…”