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Disease and treatment

Researchers have found a key to fighting degenerative diseases

People with cancer or infections are often attacked quickly and aggressively, whereas people with neurodegenerative diseases deteriorate slowly. Nevertheless, this slow decline of body and mind is almost unavoidable since these diseases are usually incurable. Researchers have now discovered what they describe as a key to preventing and curing neurodegenerative diseases such as multiple sclerosis and Parkinson’s disease.

We have become increasingly better at treating people with acute diseases, but the number of people with chronic diseases has grown. Consequently, the hunt has intensified to stop diseases in which people’s condition deteriorates continually over many years. New results show that some of these diseases can potentially be stopped – especially degenerative diseases of the central nervous system (neurodegenerative). The key is a signal receptor called liver X receptor β (LXRβ).

“Contrary to what the name might suggest, these receptors are present throughout the body, but we are specifically investigating their role as signal receptors for hormones and fatty acids in the nucleus of brain cells. LXRβ seems to play a key role in various neurodegenerative diseases. Influencing the receptor in specific ways appears to trigger protection against these diseases, which are caused by excessive activity in the brain’s immune system, such as Parkinson's disease, multiple sclerosis and optic neuritis,” explains a main author, Jan-Åke Gustafsson, Professor, Karolinska Institutet, Stockholm, Sweden.

Water channels malfunction

Liver X receptors (LXRs) expressed in the brain play a key role in maintaining cerebrospinal fluid and the health of neurons, including those that produce dopamine. These are the neurons that are destroyed in Parkinson’s disease. In their latest experiments, the researchers focused on the role of LXRs in the retina.

“The retina is an extension of the brain. Like the brain, the retina degenerates naturally with age, causing several retinal diseases, including optic neuritis, calcification, macular degeneration and glaucoma. In our new experiments, we found that the LXRs are expressed in the retina and optic nerve and that a loss of LXRβ leads to a loss of retinal ganglion cells, which retrieve information from the photosensitive cells.”

The experiments involved removing the gene encoding LXRβ in mice, causing them to lose ganglion cells in their eyes. Using a staining technique, the researchers discovered the mechanism: the mice were lacking aquaporin 4, an important protein in the cell membranes.

“The experiments clearly showed that losing the LXRs initiates the degeneration of the optic nerve. This confirms once again that LXRβ is a promising target for treating people with neurodegenerative diseases and, in this case, specific retinal degenerative diseases. These include both eye diseases arising independently and ones resulting from such chronic diseases as multiple sclerosis and diabetes,” explains a co-author, Margaret Warner, Department of Biology and Biochemistry at the University of Houston.

Enormous untapped potential

The new research is specifically interesting in explaining how degenerative eye disorders such as optic neuritis develop. Indeed, much research suggests that understanding optic neuropathy may be the key to more broadly understanding how neurodegenerative diseases generally develop – which may ultimately lead to new therapies to treat people with Alzheimer’s or Parkinson’s.

“A genetic loss of LXRβ in mice increases the amyloid plaques known in neurodegenerative diseases, and LXRβ is therefore a potential therapeutic target for the diseases caused by excessive activity in the brain's immune system. This applies to Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis.”

Previous experiments in mice have also confirmed the enormous potential of substances that can activate LXRs. These have successfully reduced the symptoms of Alzheimer’s disease and lowered cholesterol levels in insulin-resistant mice, thus inhibiting the development of arteriosclerosis and lowering blood glucose. These substances have even been shown to suppress the spread of prostate cancer and breast cancer in mice.

“The effects of LXRs have only been shown in mice, so we do not yet know whether LXRs will benefit people. One major challenge in mice has also been that the side-effects of the potential drugs increase triglycerides in the blood. Efforts are therefore being made to develop new substances without these undesirable side-effects, so these substances can hopefully be used safely in treating people.”

Retinal and optic nerve degeneration in liver X receptor β knockout mice” has been published in Proceedings of the National Academy of Sciences of the United States of America. In 2016, the Novo Nordisk Foundation awarded a grant to Jan-Åke Gustafsson for the project Multiple Functions of Oxysterol Receptors in Modulation of Neurodegeneration.

Jan-Åke Gustafsson
Professor, senior
Nuclear receptors (NRs) are ligand-activated transcription factors that encompass receptors for steroid hormones as well as receptors acting as sensors of metabolic compounds such as oxysterols and fatty acids. NRs can control intermediary metabolism as well as cellular proliferation and there is a growing appreciation that NRs could be more widely used as targets for treatment of various diseases. We focus our research on the estrogen receptors (ERs) and the liver X receptors (LXRs). Crucial for our research are mouse models with specific deletions of the receptors and we have shown that the subtypes often have distinct and sometimes even opposite roles. The role of ERs is specifically addressed in relation to breast, prostate and colon cancer and a concept of yin and yang has emerged; ERβ having anti-proliferative pro-differentiative effects. An anti-proliferative effect of LXRβ in colon has also been demonstrated. Our recent studies suggest that diseases of the CNS like Parkinson´s disease and ALS may involve a component of aberrant LXRβ signaling. LXRβ is indicated to play a protective role also in the prevention of bone diseases. We have now generated floxed ERα, ERβ, LXRα and LXRβ mice that will be used to knock out the receptors in selected tissues by using the Cre/LoxP system in order to further advance our understanding of these receptors.
Margaret Warner
Professor
Dr. Margaret Warner leads a research group focused on the study of three soluble ligand-activated receptors in health and disease: estrogen receptor beta (ERβ), liver X receptor beta (LXRβ) and aryl hydrocarbon receptor. Studies with ERβ led to the discovery of a pathway in which dihydrotestosterone is converted into 3β-Adiol, an ERβ agonist. The pathway revealed a novel role for dihydrotestosterone in the prostate i.e., in addition to being a potent androgen, it is a precursor of an estrogen. The team is investigating the value of ERβ as a target for treatment of breast and prostate cancer. All three receptors are involved in regulation of the immune system. Both ERβ and LXRβ play key roles in the central nervous system and appear to offer protection against neurodegenerative diseases caused by over activity of the brain’s immune system. These include Parkinson’s disease, amyotropic lateral sclerosis and multiple sclerosis. Prior to joining the University of Houston’s Center for Nuclear Receptors and Cell Signaling (CNRCS), Warner worked in close collaboration with professor Jan-Åke Gustafsson at the Karolinska Institutet in Stockholm, Sweden. Warner is a member of the CNRCS founding faculty and shares a research group with Gustafsson.