Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer's Disease?

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aβ) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione-electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies.

Keywords: Alzheimer’s disease; RALBP1; Rlip; mitochondrial dysfunction; neurodegeneration; oxidative stress.

Figure 1

Structure, interactions, and functions of Rlip. Rlip is a 76 kDa multi-domain protein which carries out or regulates a variety of functions. The major resulting endpoints of Rlip activity are enumerated and illustrated as separate pathways. These include (1) mitochondrial fission, (2) membrane remodeling activities, (3) efflux of glutathione conjugates, (4) receptor regulation via endocytosis, and (5) stress response.

Figure 2

Model of Rlip in mitochondrial health, oxidative stress and DNA damage. The left panel depicts cellular conditions when Rlip is abundant. Under this scenario, mitochondria are healthy and producing minimal ROS, 4-HNE is cleared from the cell, Aβ and Tau are degraded, and the DNA is not subjected to insult. The right panel depicts cellular conditions of Rlip deficiency. Unhealthy mitochondria emit greater ROS, leading to increased 4-HNE production. This 4-HNE is inefficiently cleared from the cell, causing accumulation. Accumulated 4-HNE can cause adducts on DNA, proteasomes, and Aβ. 4-HNE adducts on both proteasomes and on Aβ can inhibit proteasomal function, inhibiting Aβ and Tau degradation and causing inflammation [50,51,52,53,54]. Aβ and p-Tau aggregation, along with neuroinflammation, can exacerbate neurodegeneration and progression to AD.

Figure 3

Model of Rlip in receptor regulation, membrane re-uptake, and neurite outgrowth. The left inset (red box) depicts roles of the Rlip and clathrin-dependent endocytosis (CDE) at a synapse. Rlip is required for CDE. Presynaptically, membrane deposited at the axon terminal following neurotransmitter exocytosis must be taken up. CDE is one method that neurons use to achieve this. Postsynaptically, the cell surface expression of many receptors is regulated by CDE. This can affect ion channel-coupled receptors, G protein-coupled receptors (GPCR), and receptor tyrosine kinases (RTK). The right inset (blue box) depicts the interaction of Rlip in the formation and maintenance of synapses. MARCKS plays a role in actin coordination and neurite outgrowth, while PSD-95 carries out several functions including extracellular and intracellular synaptic anchoring and receptor regulation.