RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease

Abstract

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/− mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/− mice. Behavioral, basic motor and sensory function tests in Rlip+/− mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/− mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.

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

“…Overall, Rlip has several structural and functional domains related to oxidative stress and mitochondrial function that maintains cellular homeostasis, and a reduction of Rlip induces oxidative stress and mitochondrial dysfunction in neurodegenerative diseases such as AD. Our initial studies revealed that a partial reduction of Rlip induced oxidative stress and mitochondrial damage in AD [ 14 ]. However, further research is still needed in order to determine the precise domain structural involvement in oxidative stress/mitochondrial function in AD.…”

“…Our recent findings show that heterozygous Rlip KO (Rlip +/− ) mice have significant increases in the dentate gyrus and hippocampus expression of Drp1 and Fis1, genes involved with mitochondrial fission, and decreased expression of the mitofusin MFN1 [ 14 ]. Electron microscopy images of hippocampal and cortical cells in Rlip +/− mice showed a larger number of smaller mitochondrial relative to controls with wild-type Rlip, indicating mitochondrial fragmentation [ 14 ]. Consistently, the activity of glutathione peroxidase, a mitochondrial antioxidant enzyme, decreased in the Rlip +/− mice, which also indicates a loss of mitochondrial function [ 14 ].…”

“…Electron microscopy images of hippocampal and cortical cells in Rlip +/− mice showed a larger number of smaller mitochondrial relative to controls with wild-type Rlip, indicating mitochondrial fragmentation [ 14 ]. Consistently, the activity of glutathione peroxidase, a mitochondrial antioxidant enzyme, decreased in the Rlip +/− mice, which also indicates a loss of mitochondrial function [ 14 ]. Together, these results suggest that the mitochondria of Rlip +/− mice may be dysfunctional, with impaired energy production and elevated leakage of ROS into the surrounding cytosol.…”

“…It is thought that this further exacerbates the mitochondrial dysfunction in a vicious positive feedback cycle; however attempts to experimentally confirm such a model have yielded mixed results [ 63 ]. Several lines of evidence support a key role for Rlip in the detoxification of 4-HNE and response to oxidative stress [ 14 , 64 , 65 ], and thus the downregulation or degradation of Rlip may increase the damage caused by the elevated ROS emission resulting from amyloid β and mitochondrial dysfunction. There is also evidence that mitochondrial ROS can trigger the production of amyloid β, which can in turn further damage mitochondria [ 66 , 67 ], providing an additional layer to positive feedback models.…”

“…Recently, we reported that mice with a heterozygous loss of Rlip (Rlip +/− ) showed cognitive impairments, increased oxidative stress, and mitochondrial abnormalities, features similar to those seen in late-onset AD [ 14 ]. Molecular markers of synaptic function, as well as mitochondrial fission, fusion, and biogenesis, were also affected in brain tissues obtained from these mice [ 14 ]. Transmission electron microscopy studies of cortical and hippocampal tissues revealed abnormalities in both the size and number of mitochondria.…”