neurodegenerative disease

ALS-Linked Protein Could Be Target for Neurodegenerative Disease Therapies

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Degradation of motor neurons, conceptual computer illustration. Motor neuron diseases are a group of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy. ALS, also referred to as Lou Gehrig’s disease, is the most common of the motor neuron diseases. [Kateryna Kon/Science Photo Library/Getty Images]

Recent research from the scientists at the University of Zurich and their collaborators elsewhere describes a neural cell culture model that sheds light on the mechanisms underlying neurodegeneration that occurs in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). They used the model to determine that neurons in both diseases express toxic levels of a protein called NPTX2, and to demonstrate how this particular protein could be a viable target for new therapies. 

Details of the study are published in Nature in a paper titled, “A model of human neural networks reveals NPTX2 pathology in ALS and FTLD.” The model, dubbed iNets, is derived from human induced pluripotent stem cells and features “synaptically connected and electrophysiologically active” neurons. According to the paper, iNets replicates the behavior of TDP-43, a protein that is overexpressed in neurodegenerative diseases including most ALS cases and about half of FTLD patients. The researchers also make a clear connection between “TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity” in both pathologies.

The model cultures can last up to a year and are easily reproduced making them ideal for studying the mechanisms of neuronal decline over time. “The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise,” said Marian Hruska-Plochan, PhD, a postdoctoral fellow in the department of quantitative biomedicine at the University of Zurich and first author on the paper. “And the flexibility of the model makes it suitable for a wide range of experimental methodologies.”

Using iNets, the scientists investigated the mechanisms of ALS and FTLD progression from initial TDP-43 protein dysfunction through to neurodegeneration. They hypothesized based on the model’s behavior that NPTX2 protein accumulation was the missing link between TDP-43 misbehavior and neuronal death. Validating that hypothesis required examining brain tissue samples from deceased ALS and FTLD patients to see if there were indeed higher levels of NPTX2 in cells containing abnormal TDP-43.

Their analysis confirmed the predicted relationship between the proteins and set the stage for the next set of experiments focused on assessing NPTX2 protein’s viability as a potential drug target for ALS and FTLD therapies. Essentially, the researchers engineered a setup where they lowered the levels of NPTX2 in neurons with TDP-43 overexpression. They found that keeping NPTX2 levels low successfully counteracted neurodegeneration in the iNets neurons. It is possible that drugs that work by targeting and reducing NPTX2 protein production could successfully halt neurodegeneration in ALS and FTLD patients.

Although these are promising predictions, it’s important to remember that the results are preliminary. “We still have a long way to go before we can bring this to the patients, but the discovery of NPTX2 gives us a clear shot of developing a therapeutic that acts at the core of the disease,” said Magdalini Polymenidou, PhD, an associate professor of biomedicine in the department of quantitative biomedicine at the University of Zurich and corresponding author on the paper. “In conjunction with two additional targets recently identified by other research teams, it is conceivable that anti-NPTX2 agents could emerge as a key component of combination therapies for ALS and FTLD in the future.

Neurodegenerative Disease Could Be Treated by Using Pexophagy to Limit Autophagy

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Neurodegenerative Disease Could Be Treated by Using Pexophagy to Limit Autophagy

Concept of scientist exploring human brain

Neurodegenerative Disease Could Be Treated by Using Pexophagy to Limit Autophagy

January 10, 2024

Credit: Feodora Chiosea / Getty Images/iStockphoto

Like all living things, cellular structures break down over time and must be recycled. In cells, this process is called autophagy. Most neurodegenerative diseases are related to the improper accumulation of cellular waste by-products. Now, for the first time, researchers at the Hospital for Sick Children (SickKids) have revealed a way to potentially reduce the amount of toxic cellular waste accumulating in patients with Zellweger Spectrum Disorder (ZSD). The researchers discovered that by genetically and pharmaceutically increasing a cell’s ability to recycle its own components it is possible to clear damaged cellular material, providing a new therapeutic target for treating ZSD. The new findings may also inform research in other neurodegenerative conditions such as Huntington’s disease and Parkinson’s disease.

The findings are published in Nature Communications in an article titled, “Upregulated pexophagy limits the capacity of selective autophagy,” and led by Peter Kim, PhD, a senior scientist in the cell biology program at SickKids, and Robert Bandsma, PhD, a scientist in the translational medicine program.

“Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components,” the researchers wrote. “Over a dozen selective autophagy pathways mediate the degradation of diverse cellular substrates, but whether these pathways can influence one another remains unknown. We address this question using pexophagy, the autophagic degradation of peroxisomes, as a model.”

ZSD is a group of rare, neurodegenerative genetic conditions caused by genetic variations that reduce the number of peroxisomes, which are the parts of cells that are responsible for, among other tasks, breaking down fats. ZSD varies in severity and is characterized by progressive neurodegeneration as well as symptoms that range from visual impairments, such as cataracts, to liver and kidney dysfunction.

Previous research from the Kim-Bandsma team found that the most common genetic variation that causes ZSD significantly increases pexophagy, causing healthy peroxisomes to get recycled alongside unhealthy ones. In the new study, Kyla Germain, PhD, a former graduate student in Kim’s and Bandsma’s labs, found that this increase in pexophagy can also prevent cells from degrading other cellular waste.

“Our work demonstrates for the first time that different cellular recycling pathways can influence one another,” Germain explained. “A cell’s recycling system has a maximum load capacity—an autophagic limit. When this limit is exceeded, toxic cellular waste will accumulate.”

After identifying this connection between different recycling pathways, researchers found they could improve the overall recycling process by increasing the autophagic limit. In doing so, they observed improved clearance of cellular waste, which opens new pathways to treat ZSD.

“These results are exciting as they show that through understanding a fundamental process that takes place in all our cells, we can potentially develop new and better treatments for a very serious condition,” said Bandsma, who is also a staff physician in the division of gastroenterology, hepatology, and nutrition at SickKids.

“We identified that protein aggregates involved in Huntington’s disease and Parkinson’s disease can also prevent the turnover of damaged peroxisomes, which means scientists may be able to target these components in patients outside the field of ZSD,” Kim said.

Looking toward the future, the Kim-Bandsma team’s next step is to take this research into a preclinical ZSD model to test various therapeutics that could either increase autophagy or inhibit pexophagy.

Researchers reveal how a common mutation causes neurodegenerative disease

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Researchers reveal how a common mutation causes neurodegenerative disease
Brian Freibaum, Ph.D., is a postdoctoral fellow in the Cell & Molecular Biology Department at St. Jude Children’s Research Hospital. 

Researchers have determined how the most common gene mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) disrupts normal cell function, providing insight likely to advance efforts to develop targeted therapies for these brain diseases. Scientists from St. Jude Children’s Research Hospital and the University of Massachusetts Medical School (UMMS) led the research, which appears today in the science journal Nature.

Investigators reported evidence the mutation interferes with the movement of RNAs and proteins into and out of the nucleus. Instructions for assembling new proteins are encoded in DNA in the cell nucleus. RNA carries this information out of the nucleus to the cytoplasm where proteins are made. The discovery reveals that the most common in ALS and FTD blocks this transfer of information, setting the stage for the deterioration and death of neurons in the brain and spinal cord.

The findings come four years after in the gene C9ORF72 were discovered and identified as the most common genetic cause of ALS, which is also known as Lou Gehrig disease. Mutations in the same gene also cause FTD, another neurodegenerative disorder that includes changes in behavior and personality as well as problems with motor function. Until now, however, how the mutation disturbed cell function was unknown.

“C9ORF72 mutations are by far the most common genetic defect associated with both ALS and FTD, so understanding how the mutation causes disease is tremendously important for efforts to develop therapies to stop or reverse the death of neurons in the brain and spinal cord of patients,” said co-corresponding author J. Paul Taylor, M.D., Ph.D., Chair of the St. Jude Department of Cell and Molecular Biology and a Howard Hughes Medical Institute investigator. “Such therapies are desperately needed since there are no treatments proven to halt or reverse the disorders. Most patients die within five years of diagnosis.”

Added co-corresponding author Fen-Biao Gao, Ph.D., professor of neurology at UMMS: “Combining a simple fruit fly model with experiments in cells donated by ALS and FTD patients was essential for discovering the disease mechanism underlying mutations in C9ORF72.”

This year ALS will be diagnosed in about 5,600 U.S. residents. Ninety percent or more of patients report no family history of the disease. C9ORF72 mutations account for 4 to 6 percent of ALS in these patients and for 25 to 40 percent of ALS in those with family histories of the disease. FTD will be identified in a similar number of individuals.

The C9ORF72 gene normally includes a short sequence of DNA that is repeated 20 times or less. In the mutant gene, however, this sequence—GGGGCC—is expanded and abnormally repeated dozens or thousands of times. The resulting RNA reflects the repetitions and can lead to abnormally shaped RNA and proteins that damage cells.

To determine how the repetitions affect the cell, co-first author Brian Freibaum, Ph.D., a St. Jude staff scientist, developed a fruit fly model of the human neurodegenerative diseases FTD and ALS that includes C9ORF72 with expanded repetitions. Flies with 58 repetitions had more severe symptoms than flies with the normal number.

Researchers in Memphis and in Worcester, MA., then divided up the work and screened more than 80 percent of the mutant fly genome to track the consequences of the C9ORF72 repetitions.

By sequentially knocking out one copy of each gene, researchers identified 18 modifier genes whose loss led to an easing or worsening of symptoms. The 18 genes were all involved in the nuclear transportation system. Some genes encoded proteins that were part of the nuclear pore complex; others were part of the machinery that coordinates the export of RNA from the nucleus and the import of proteins needed for the nucleus to function properly.

Checking neurons generated from patients with the C9ORF72 mutation revealed a buildup of RNA in the nucleus of cells. When researchers compared RNA concentration inside and outside the nucleus, they found RNA density was about 35 percent greater in neurons from patients with the mutation than in those without. The study included neurons generated from five patients with C9ORF72 mutations and three without. The mutation did not have a similar impact on RNA concentrations in skin fibroblast cells from the same patients. That suggests the damage caused by C9ORF72 mutation is limited to brain cells.

“While work continues to determine exactly why the newly identified defect is toxic to neurons, this study reveals the key defect we need to reverse in treatment, for example by knocking out or silencing the ,” said Taylor, whose research focuses on reducing death and disability associated with neurological disease.

Pharmacological Treatment of Parkinson Disease A Review.

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Importance  Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life.

Objective  To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea.

Evidence Review  References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic.

Results  Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies.

Conclusions and Relevance  Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.

Alzheimer’s, cognitive decline and neurodegenerative disease linked to too much toxic ‘free copper’ in blood.

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Copper is an essential dietary mineral that must be maintained at levels that are in proper balance with other essential dietary minerals like zinc. But having too much “free copper,” also known as bio-unavailable copper, circulating in the blood may indicate, or even be the cause of, some serious health problems, including cognitive decline, neurodegenerative disease and Alzheimer’s.

copper

A 2008 study published in the journal Current Opinion in Clinical Nutrition and Metabolic Care reveals some of the more serious adverse effects of having too much circulating free copper. Specifically with regard to Wilson’s disease, Alzheimer’s and other forms of neurodegeneration and cognitive decline, copper was found to play a major role in triggering the inflammation, autoimmunity and fibrosis linked to these and other diseases.

Researchers from the University of Michigan in Ann Arbor uncovered data that suggests having too much free copper in the blood may be involved in actual disease pathogenesis, meaning free copper may be one of the primary pathways through which disease emerges and takes hold. Based on this assessment, the team focused on ways to eliminate excess copper from the body and thus mitigate both the presence and likelihood of disease.

A similar but unrelated study published two years later in Clinical Neurophysiology, the official journal of the International Federation of Clinical Neurophysiology, by researchers from the Institute of Cognitive Sciences and Technologies in Italy spells this out even more clearly, differentiating between total copper levels and free copper levels, and their respective effects on neurodegeneration.

Not all copper is harmful, explains this study in full clarity, but rather just the free copper that is loosely transported by micronutrients in the body when it is not properly absorbed. Bioavailable copper, on the other hand, is absolutely critical for strong immunity, disease resistance, blood cleansing and other important functions — copper itself, in other words, is not the enemy.

“Copper maintains mineral balance, thus a balanced pH with normal blood viscosity, by functioning as the primary antioxidant in the body,” explains UnveilingThem.com. “Iron replaces copper in the blood and tissue proteins and accumulates in multiple locations of the body, causing destruction and accelerating aging. Bio-available copper must be replenished to restore health and longevity — to repaid the DNA damage.”

Too much free copper could be the result of Alzheimer’s, not the cause

Copper, then, is not the problem — it is an accumulation of bio-unavailable copper in the blood that is the problem. But what causes this? The two previously mentioned studies suggest that too much free copper is a cause of Alzheimer’s and other forms of neurodegeneration, and thus must be mitigated through drugs or other methods. But other studies suggest the inverse, that neurodegeneration is a cause of too much free copper.

A 2011 study published in the International Journal of Alzheimer’s Disease suggests that the bioavailability of dietary copper is thrown off kilter as a direct result of Alzheimer’s, which puts the issue of copper toxicity into a whole different perspective. In other words, degenerative disease may prevent the body from using dietary copper, instead turning it into toxic free copper.

A good comparative illustration is the issue of high cholesterol and the prominent recommendation that people use statin drugs to lower it. Contrary to conventional thinking on the subject, too much circulating cholesterol does not mean that the cholesterol itself is harmful. It means that systemic inflammation is preventing that cholesterol from being properly utilized and absorbed, which means that dietary changes to stop that inflammation, not cholesterol-lowering drugs, are needed to address the problem.

Sources for this article include:

http://science.naturalnews.com

http://science.naturalnews.com

http://www.unveilingthem.com