“Validation of qPCR reference genes in lymphocytes from patients with amyotrophic lateral sclerosis” has been published in the journal PLOS Medicine. This work was supported in part by JPND through the SOPHIA project, selected in the 2011 Biomarkers call.
A gene variant that produces red hair and fair skin in humans and in mice, which increases the risk of the dangerous skin cancer melanoma, may also contribute to the known association between melanoma and Parkinson’s disease. Reseachers report that mice carrying the red hair variant of the melanocortin 1 receptor (MC1R) gene have reduced production of the neurotransmitter dopamine in the substantia nigra — the brain structure in which dopamine-producing neurons are destroyed in Parkinson’s disease (PD) — and are more susceptible to toxins known to damage those neurons.
This work was published in Annals of Neurology. Inherited variants of the MC1R gene determine skin pigmentation, with the most common form leading to greater production of the darker pigment called eumelanin and the red-hair-associated variant, which inactivates the gene’s function, increasing production of the lighter pigment called pheomelanin. Not only does pheomelanin provide less protection from ultraviolet damage to the skin than does eumelanin, but a previous study found it also may directly contribute to melanoma development.
While patients with Parkinson’s disease have a reduced risk of developing most types of cancer, their higher-than-expected risk of melanoma is well recognized, as is the increased risk of PD in patients with melanoma.
The team’s experiments showed that, in mice with the common form of MC1R, the gene is expressed in dopamine-producing neurons in the substantia nigra. The red-haired mice in which the gene is inactivated because of a mutation were found to have fewer dopamine-producing neurons and as they aged developed a progressive decline in movement and a drop in dopamine levels. They also were more sensitive to toxic substances known to damage dopamine-producing neurons and had indications of increased oxidative stress in brain structures adjacent to the substantia nigra. Treatment with a substance that increases MC1R signaling reduced the susceptibility of mice with the common variant to a neurotoxin, further supporting a protective role for the gene’s activity.
Paper: “The melanoma-linked ‘redhead’ MC1R influences dopaminergic neuron survival”
Reprinted from materials provided by Massachusetts General Hospital.
“Therapeutic Strategies Under Development Targeting Inflammatory Mechanisms in Amyotrophic Lateral Sclerosis” has been published in Molecular Neurobiology. This work was supported in part by JPND through the DAMNDPATHS project, selected in the 2013 Cross-Disease Analysis call.
Abnormality with special cells that wrap around blood vessels in the brain leads to neuron deterioration, possibly affecting the development of Alzheimer’s disease, a new study reveals.
“Gatekeeper cells” called pericytes surround blood vessels, contracting and dilating to control blood flow to active parts of the brain.
Published in Nature Neuroscience, this was the first study to use a pericyte-deficient mouse model to test how blood flow is regulated in the brain. The goal was to identify whether pericytes could be an important new therapeutic target for treating neuron deterioration.
Pericyte dysfunction suffocates the brain, leading to metabolic stress, accelerated neuronal damage and neuron loss, the researchers say. To test the theory, they stimulated the hind limb of young mice deficient in gatekeeper cells and monitored the global and individual responses of brain capillaries, the smallest blood vessels in the brain. The global cerebral blood flow response to an electric stimulus was reduced by about 30 percent compared to normal mice, denoting a weakened system.
Relative to the control group, the capillaries of pericyte-deficient mice took 6.5 seconds longer to dilate. Slower capillary widening and a slower flow of red blood cells carrying oxygen through capillaries means it takes longer for the brain to get its fuel.
As the mice turned 6 to 8 months old, global cerebral blood flow responses to stimuli progressively worsened. Blood flow responses for the experimental group were 58 percent lower than that of their age-matched peers. In short, with age, the brain’s malfunctioning vascular system exponentially worsens.
The researchers say that their study brings new information to the study of Alzheimer’s disease and ALS. Previous studies have shown that pericytes die in Alzheimer’s and ALS patients, and this study demonstrated that the death of these pericytes restricts blood flow and oxygen to the brain. The next step, they say, will be to try to reveal what kills pericytes in Alzheimer’s and ALS in the first place.
Paper: “Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain”
Reprinted from materials provided by University of Southern California.
“Discovery and systematic functional validation of Parkinson’s disease genes from exome sequencing (S1.003)” has been published in Neurology. This work was supported in part by JPND through the 3DMiniBrain project, selected in the 2015 JPco-fuND call.
In a study of mice and monkeys, researchers have shown that they could prevent and reverse some of the brain injury caused by the toxic form of the protein tau. The results, published in Science Translational Medicine, suggest that the study of compounds, called tau antisense oligonucleotides, that are genetically engineered to block a cell’s assembly line production of tau, might be pursued as an effective treatment for a variety of disorders.
Cells throughout the body normally manufacture tau proteins. In several disorders, toxic forms of tau clump together inside dying brain cells and form neurofibrillary tangles, including Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy. Currently there are no effective treatments for combating toxic tau.
Antisense oligonucleotides are short sequences of DNA or RNA programmed to turn genes on or off. The researchers tested sequences designed to turn tau genes off in mice that are genetically engineered to produce abnormally high levels of a mutant form of the human protein. Tau clusters begin to appear in the brains of 6-month-old mice and accumulate with age. The mice develop neurologic problems and die earlier than control mice.
Injections of the compound into the fluid-filled spaces of the mice brains prevented tau clustering in 6-9 month old mice and appeared to reverse clustering in older mice. The compound also caused older mice to live longer and have healthier brains than mice that received a placebo. In addition, the compound prevented the older mice from losing their ability to build nests.
Currently researchers are conducting early phase clinical trials on the safety and effectiveness of antisense oligonucleotides designed to treat several neurological disorders, including Huntington’s disease and amyotrophic lateral sclerosis (ALS).
Further experiments on non-human primates suggested that the antisense oligonucleotides tested in mice could reach important areas of larger brains and turn off tau. In comparison with a placebo, two spinal tap injections of the compound appeared to reduce tau protein levels in the brains and spinal cords of Cynomologus monkeys. As the researchers saw with the mice, injections of the compound caused almost no side effects.
Nevertheless, the researchers concluded that the compound needs to be fully tested for safety before it can be tried in humans. They are taking the next steps towards translating it into a possible treatment for a variety of tau related disorders.
Paper: “Abnormal neurogenesis and cortical growth in congenital heart disease”
Reprinted from materials provided by NIH/NINDS.
“FEWDON-MND syndrome (finger extension weakness and downbeat nystagmus): A novel motor neuron disorder?” has been published in the journal Muscle & Nerve. This work was supported in part by JPND through the STRENGTH project, selected in the 2012 Risk Factors call.
Researchers have discovered a common genetic variant that greatly impacts normal brain aging, starting at around age 65, and may modify the risk for neurodegenerative diseases. The findings could point toward a novel biomarker for the evaluation of anti-aging interventions and highlight potential new targets for the prevention or treatment of age-associated brain disorders such as Alzheimer’s disease.
The study was published online in the journal Cell Systems.
Previous studies have identified individual genes that increase one’s risk for various neurodegenerative disorders, such as apolipoprotein E (APOE) for Alzheimer’s disease. In the current study, researchers analyzed genetic data from autopsied human brain samples taken from 1,904 people without neurodegenerative disease. First, the researchers looked at the subjects’ transcriptomes (the initial products of gene expression), compiling an average picture of the brain biology of people at a given age. Next, each person’s transcriptome was compared to the average transcriptome of people at the same age, looking specifically at about 100 genes whose expression was found to increase or decrease with aging. From this comparison, the researchers derived a measure that they call differential aging: the difference between an individual’s apparent (biological) age and his or her true (chronological) age. The researchers then searched the genome of each individual, looking for genetic variants that were associated with an increase in differential age. Variants of a gene called TMEM106B, the researchers say, appeared to have an impact on the speed of brain aging starting at age 65.
The researchers found a second variant — inside the progranulin gene — that contributes to brain aging, though less so than TMEM106B. Progranulin and TMEM106B are located on different chromosomes but are involved in the same signaling pathway. Both have also been associated with a rare neurodegenerative disease called frontotemporal dementia.
Paper: “Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phénotypes”
Reprinted from materials provided by Columbia University Medical Center.