Removing protein ‘garbage’ in nerve cells may help control 2 neurodegenerative diseases

Neuroscientists at Georgetown University Medical Center say they have new evidence that challenges scientific dogma involving two fatal neurodegenerative diseases — amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) — and, in the process, have uncovered a possible therapeutic target as a novel strategy to treat both disorders.

The study, posted online in the Journal of Biological Chemistry, found that the issue in both diseases is the inability of the cell’s protein garbage disposal system to “pull out” and destroy TDP-43, a powerful, sometimes mutated gene that produces excess amounts of protein inside the nucleus of a nerve cell, or neuron.

"This finding suggests that if we’re able to ‘rev up’ that clearance machinery and help the cell get rid of the bad actors, it could possibly reduce or slow the development of ALS and FTD," says the study’s lead investigator, neuroscientist Charbel E-H Moussa, MB, PhD. "The potential of such an advance is very exciting." He cautions, though, that determining if this strategy is possible in humans could take many years and will involve teams of researchers.

The way to rev up protein disposal is to add parkin — the cell’s natural disposal units — to brain cells. In this study, Moussa and his colleagues demonstrated in two animal experiments that delivering parkin genes to neurons slowed down ALS pathologies linked to TDP-43.”

Moussa says that his study further demonstrates that clumps known as “inclusions” of TDP-43 protein found inside neuron bodies in both disorders do not promote these diseases, as some researchers have argued.

What happens in both diseases is that this protein, which is a potent regulator of thousands of genes, leaves the nucleus and collects inside the gel-like cytoplasm of the neuron. In ALS, also known as Lou Gehrig’s disease, this occurs in motor neurons, affecting movement; in FTD, it occurs in the frontal lobe of the brain, leading to dementia.

"In both diseases, TDP-43 is over-expressed or mutated, and the scientific debate has been whether loss of TDP-43 in the nucleus or gain of TDP-43 in the cytoplasm is the problem," Moussa says.

"Our study suggests TDP-43 in the cell cytoplasm is deposited there in order to eventually be destroyed — without contributing to disease — and that TDP-43 in the nucleus is causing the damage," he says. "Because so much protein is being produced, the cell can’t keep up with removing these toxic particles in the nucleus and the dumping of them in the cytoplasm. There may be a way to fix this problem."

Moussa has long studied parkin, a molecule best known, when mutated and inactive, for its role in a familial form of Parkinson’s disease. He has studied it in Alzheimer’s disease and other forms of dementia. His hypothesis, which he has demonstrated in several recently published studies, is that parkin could help remove the toxic fragments of amyloid beta protein that builds up in the brains of Alzheimer’s disease patients.

What’s more, he developed a method to clear this amyloid beta when it begins to build up in neurons — a gene therapy strategy he has shown works in rodents. Work continues on this potential therapy.

In this study, Moussa found that parkin “tags” TDP-43 protein in the nucleus with a molecule that takes it from the nucleus and into the cytoplasm of the cell. “This is good. If TDP-43 is in the cytoplasm, it will prevent further nuclear damage and deregulation of genetic materials that determine protein identity,” he says.

"This discovery challenges the dogma that accumulation of TDP-43 in the cytoplasm is," Moussa says. "We think parkin is tagging proteins in the nucleus for destruction, but there just isn’t enough parkin around — compared with over-production of TDP-43 — to do the job."

Moussa says his next research steps will be to inject a drug that activates parkin to see whether that can prolong the lifespan and reduce motor defects in mice with ALS.

(Image: iStock)

New immune therapy successfully treats brain tumors in mice

Using an artificial protein that stimulates the body’s natural immune system to fight cancer, a research team at Duke Medicine has engineered a lethal weapon that kills brain tumors in mice while sparing other tissue. If it can be shown to work in humans, it would overcome a major obstacle that has hampered the effectiveness of immune-based therapies.

The protein is manufactured with two arms – one that exclusively binds to tumor cells and another that snags the body’s fighter T-cells, spurring an attack on the tumor. In six out of eight mice with brain tumors, the treatment resulted in cures, according to findings published Dec. 17, 2012, in the Proceedings of the National Academy of Sciences.

"This work represents a revival of a somewhat old concept that targeting cancer with tumor-specific antigens may well be the most effective way to treat cancer without toxicity," said senior author John H. Sampson, M.D., PhD, a neurosurgeon at The Preston Robert Tisch Brain Tumor Center at Duke. "But there have been problems with that approach, especially for brain tumors. Our therapeutic agent is exciting, because it acts like Velcro to bind T-cells to tumor cells and induces them to kill without any negative effects on surrounding normal tissues."

Sampson and colleagues focused on the immune approach in brain tumors, which are notoriously difficult to treat. Despite surgery, radiation and chemotherapy, glioblastomas are universally fatal, with a median survival of 15 months.

Immunotherapies, in which the body’s B-cells and T-cells are triggered to attack tumors, have shown promise in treating brain and other cancers, but have been problematic in clinical use. Treatments have been difficult to administer at therapeutic doses, or have spurred side effects in which the immune system also attacks healthy tissue and organs.

Working to overcome those pitfalls, the Duke-led researchers designed a kind of connector - an artificial protein called a bispecific T-cell engager, or BiTE – that tethers the tumor to its killer. Their newly engineered protein includes fractions of two separate antibodies, one that recruits and engages the body’s fighter T-cells and one that expressly homes in on an antigen known as EGFRvIII, which only occurs in cancers.

Once connected via the new bispecific antibody, the T-cells recognize the tumor as an invader, and mount an attack. Normal tissue, which does not carry the tumor antigen, is left unscathed.

Mayo Clinic Researchers Uncover Toxic Interaction in Neurons that Leads to Dementia and ALS

Researchers at Mayo Clinic in Florida have uncovered a toxic cellular process by which a protein that maintains the health of neurons becomes deficient and can lead to dementia. The findings shed new light on the link between culprits implicated in two devastating neurological diseases: frontotemporal dementia and amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease. The study is published Dec. 10 in the online issue of Proceedings of the National Academy of Sciences.

There is no cure for frontotemporal dementia, a disorder that affects personality, behavior and language and is second only to Alzheimer’s disease as the most common form of early-onset dementia. While much research is devoted to understanding the role of each defective protein in these diseases, the team at Mayo Clinic took a new approach to examine the interplay between TDP-43, a protein that regulates messenger ribonucleic acid (mRNA) — biological molecules that carry the information of genes and are used by cells to guide protein synthesis — and sortilin, which regulates the protein progranulin.

"We sought to investigate how TDP-43 regulates the levels of the protein progranulin, given that extreme progranulin levels at either end of the spectrum, too low or too high, can respectively lead to neurodegeneration or cancer," says the study’s lead investigator, Mercedes Prudencio, Ph.D., a neuroscientist at the Mayo Clinic campus in Florida.

The neuroscientists found that a lack of the protein TDP-43, long implicated in frontotemporal dementia and amyotrophic lateral sclerosis, leads to elevated levels of defective sortilin mRNA. The research team is the first to identify significantly elevated levels of the defective sortilin mRNA in autopsied human brain tissue of frontotemporal dementia/TDP cases, the most common subtype of the disease.

Yeast Protein Breaks up Amyloid Fibrils and Disordered Protein Clumps In Different Ways

Several fatal brain disorders, including Parkinson’s disease, are connected by the misfolding of specific proteins into disordered clumps and stable, insoluble fibrils called amyloid. Amyloid fibrils are hard to break up due to their stable, ordered structure. For example, a-synuclein forms amyloid fibrils that accumulate in Lewy Bodies in Parkinson’s disease. By contrast, protein clumps that accumulate in response to environmental stress, such as heat shock, possess a less stable, disordered architecture.

Hsp104, an enzyme from yeast, breaks up both amyloid fibrils and disordered clumps. In the most recent issue of Cell, James Shorter, PhD, assistant professor of Biochemistry and Biophysics, and colleagues from the Perelman School of Medicine, University of Pennsylvania, show that Hsp104 switches mechanism to break up amyloid versus disordered clumps. For stable amyloid-type structures, Hsp104 needs all six of its subunits, which together make a hexamer, to pull the clumps apart. By contrast, for the more amorphous, non-amyloid clumps, Hsp104 required only one of its six subunits.

Study Confirms AKT1 Genotype Contributes to Risk of Cannabis Psychosis

The ability of cannabis to produce psychosis is an important public health concern. Some studies have suggested that cannabis exposure during adolescence may increase the risk of developing schizophrenia.

For these reasons, it would be valuable if a biological test could be developed that predicted the risk of developing psychosis in people who abuse cannabis or use marijuana as a medication.

A recent study has implicated a variation in the gene that codes for a protein called RAC-alpha serine/threonine-protein kinase in the risk for cannabis psychosis. However, independent verification of these finding is critical for genetic associations with complex genetic traits, like cannabis-related psychosis, because these findings are difficult to replicate.

Dr Forti’s team carried out a case control study to investigate variation in the AKT1 gene and cannabis use in increasing the risk of psychosis.

“We studied the AKT1 gene as this is involved in dopamine signaling which is known to be abnormal in psychosis. Our sample comprised 489 patients with their first episode of psychosis and 278 healthy controls,” explained Dr Forti, who, with colleagues, reports on the results in the journal Biological Psychiatry.

Unique protein bond enables learning and memory

Two proteins have a unique bond that enables brain receptors essential to learning and memory to not only get and stay where they’re needed, but to be hauled off when they aren’t, researchers say.

NMDA receptors increase the activity and communication of brain cells and are strategically placed, much like a welcome center, at the receiving end of the communication highway connecting two cells. They also are targets in brain-degenerating conditions such as Alzheimer’s and Parkinson’s.

In a true cradle-to-grave relationship, researchers have found the scaffolding protein, SAP102, which helps stabilize the receptor on the cell surface, binds with a subunit of the NMDA receptor called GluN2B at two sites, said Dr. Bo-Shiun Chen, neuroscientist at the Medical College of Georgia at Georgia Health Sciences University.

While one binding site is the norm, these proteins have one that’s stronger than the other. When it’s time for the normal receptor turnover, the stronger bond releases and the lesser one shuttles the receptor inside the cell for degradation or recycling.

“One binding site is involved in stabilizing the receptor on the cell surface and the other is important in removing the receptor. We think it’s a paradigm shift; we’ve never thought about the same scaffolding protein having two roles,” said Chen, corresponding author of the study in the journal Cell Reports.