Enhancing the brain’s own clean-up crews could be a strategy for handling the toxic proteins driving several neurodegenerative diseases, new research suggests.
Astrocytes, an abundant supportive cell type in the brain, are better than neurons at disposing of mutant huntingtin, the toxic protein that drives Huntington’s disease pathology, Xiao-Jiang Li and colleagues report in this week’s PNAS.
One reason why astrocytes are better at toxic protein defense than neurons is: they have less of an inhibitory protein called HspBP1. The scientists show that using CRISPR/Cas9 to “knock down” HspBP1 can help neurons get rid of mutant huntingtin and reduce early pathological signs.
Emory University School of Medicine researchers have developed tools that enable them to detect small proteins called granulins for the first time inside cells. Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously unclear.
FTD is an incurable neurodegenerative disease and the most common type of dementia in people younger than 60. Genetic variants in the granulin gene are also a risk factor for Alzheimer’s disease and Parkinson’s disease, suggesting this discovery may have therapeutic potential for a broad spectrum of age-related neurodegenerative diseases.
The results were published August 9 by the journal eNeuro (open access).
Thomas Kukar, PhD
Some neuroscientists believed that granulins were made outside cells, and even could be toxic under certain conditions. But with the newly identified tools, the Emory researchers can now see granulins inside cells within lysosomes, which are critical garbage disposal and recycling centers. The researchers now propose that granulins have important jobs in the lysosome that are necessary to maintain brain health, suppress neuroinflammation, and prevent neurodegeneration.
Problems with lysosomes appear in several neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
“A lysosomal function for granulins is exciting and novel. We believe it may provide an explanation why decreased levels of granulins are linked to multiple neurodegenerative diseases, ranging from frontotemporal dementia to Alzheimer’s,” says senior author Thomas Kukar, PhD, assistant professor of pharmacology and neurology and the Emory University Center for Neurodegenerative Disease. Read more
The drug target VMAT2 has appeared in biomedical news lately because of a pair of FDA approvals. One medicine treats the iatrogenic movement disorder tardive dyskinesia, the first approved to do so, and the other is for symptoms of Huntington’s disease.
Gary Miller, PhD
When Emory folks see VMAT2, they should think of two things: the neurotransmitter dopamine, and Parkinson’s research conducted by Gary Miller and his colleagues. They have made a case that activators of VMAT2 would be beneficial in Parkinson’s, but the drugs in the news were inhibitors, and presumably would make Parkinson’s worse.
VMAT2 (vesicular monoamine transporter 2) is responsible for transporting dopamine into synaptic vesicles, tiny packages for delivery. As Miller’s lab has shown, mice deficient in VMAT2 can be a model for the non-motor and motor aspects of Parkinson’s. In these mice, not only are certain nervous system functions impaired, but the dopamine packaging problem inflicts damage on the neurons.
Miller’s more recent work on a related molecule called SV2C is puzzling, but intriguing. The gene encoding SV2C had attracted attention because of its connection to the striking ability of cigarette smoking to reduce Parkinson’s risk, possibly mediated by nicotine’s effect on dopamine in the brain.
I say puzzling because SV2C’s role in brain cells can’t be described as easily as VMAT2’s. Read more
Posted on May 10, 2017
Using one to see into the other. Left: canister for breath sample. Right: basal ganglia, a region of the brain usually affected by Parkinson’s.
Scientists think that it may be possible to detect signs of Parkinson’s disease through a breath test.
The Michael J. Fox Foundation for Parkinson’s Research is supporting a clinical study at Emory that will probe this idea. Neuro-immunologist Malu Tansey is working with Hygieia, a Georgia-based company that has developed technology for analyzing volatile organic compounds present in exhaled air.
From the MJFF’s blog:
By collecting and analyzing breath samples in 100 people (50 non-smoking early-stage PD patients and 50 age and sex-matched controls), the researchers hope to define a unique inflammatory PD-specific breath fingerprint that could be used to predict and monitor disease in combination with blood analyses of conventional or newly discovered biomarkers.
“We hypothesize that breath volatile organic compounds (BVOCs) fingerprinting can enable sensitive and specific measures of ongoing inflammation and other processes implicated in the development and/or progression of PD, and thus could represent an early detection tool,” Tansey says.
If results indicate moving forward, Tansey says it will be important to compare the breath sample method against blood tests for inflammatory markers. Other reports on the breath test approach for Parkinson’s have been encouraging. Read more
It’s sweet, it’s safe, and it looks like it could save neurons. What is it? Trehalose.
Trehalose is a natural sugar.
This natural sugar is used in the food industry as a preservative and flavor enhancer (it’s in Taco Bell’s meat filling). And curiously, medical researchers keep running into trehalose when they’re looking for ways to fight neurodegenerative diseases.
A recent example from Emory’s Department of Pharmacology: Chris Holler, Thomas Kukar and colleagues were looking for drugs that might boost human cells’ production of progranulin (PGRN), a growth factor that keeps neurons healthy. Mutations in the progranulin gene are a common cause of frontotemporal dementia.
The Emory scientists discovered two leads: a class of compounds called mTOR inhibitors — the transplant drug rapamycin is one — and trehalose. The team decided to concentrate on trehalose because it increased PGRN levels in neuronal and non-neuronal cell types, unlike the mTOR inhibitors. Their results were published at the end of June in Molecular Neurodegeneration.
The team confirmed their findings by examining the effects of trehalose on cells derived from patients with progranulin mutations. This paper is the first to include results from Emory’s Laboratory of Translational Cell Biology, which was established in 2012 to facilitate this type of “disease in a dish” approach. Cell biologists Charles Easley, Wilfried Rossoll and Gary Bassell from the LTCB, and neurologists Chad Hales and William Hu from the Center for Neurodegenerative Disease are co-authors.
Those of us who are old enough to remember vinyl records will recall how a scratch can cause the same sounds to repeat many times. A similar type of genetic glitch causes neurodegenerative diseases such as Huntingtonâ€™s and several forms of spinocerebellar ataxia.
Huntingtonâ€™s and the spinocerebellar ataxias are known as â€œpolyglutamineâ€ diseases. In each, the affected gene has a stretch where the same three DNA letters are repeated several times — more than usual. As a result, the protein encoded by the affected gene has a patch, where only the building block glutamine can be found, disrupting that proteinâ€™s usual functions in the body.
Geneticist Xiao-Jiang Li and colleagues recently published a paper in Cell Reports that may explain why more aggressive juvenile-onset forms of polyglutamine diseases have different symptoms and pathology. Read more
Emory researchers led by neurologist Manuel Yepes, MD have identified a protein released by neurons while the brain is recovering from a stroke.Â The results were published online today inÂ Journal of Neuroscience.
The protein, called urokinase-type plasminogen activator or uPA, has been approved by the FDA to dissolve blood clots in the lungs. It has been tested in clinical trialsÂ in some countriesÂ as a treatment for acute stroke.
The Emory teamâ€™s findings suggest that in stroke, uPAâ€™s benefits may extend beyond the time when doctorsâ€™ principal goal is dissolving the blood clot that is depriving the brain of blood.
Instead, uPA appears to help brain cells recover from the injuries induced by loss of blood flow. Treating mice with uPA after an experimental stroke can improve their recovery of motor function, the researchers found.