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.