mitochondria

CIRM-funded Stanford study finds potential diagnostic tool, treatment for Parkinson’s

/ Yimy Villa / Leave a comment
Dr. Xinnan Wang, a neurosurgeon and author of a study that has identified a molecular pathway apparently responsible for the death of dopaminergic neurons that causes the symptoms of Parkinson’s.

Of the various neurodegenerative diseases, Parkinson’s is the second most common and affects 35 million people world wide. It is caused by the gradual breakdown of dopaminergic neurons in the brain, which are a type of cell that produce a chemical in your brain known as dopamine.  This decrease in dopamine can cause complications such as uncontrollable shaking of the hands, slowed movement, rigid muscles, loss of automatic movements, speech changes, bladder problems, constipation, and sleep disorders.

Although 5-10% of cases are the result of genetically inherited mutations, the vast majority of cases are sporadic, often involving complex interactions of multiple unknown genes and environmental factors. Unfortunately, it is this unknown element that make the disease very difficult to detect early on in the majority of patients.

However, in a CIRM funded study, Dr. Xinnan Wang and her team at Stanford University were able to pinpoint a molecular defect that seems almost universal in patients with Parkinson’s and those at high risk of acquiring it. This could prove to be a way to detect Parkinson’s in its early stages and before symptoms start to manifest. Furthermore, it could also be used to evaluate a potential treatment’s effectiveness at preventing or stalling the progression of Parkinson’s.

In a Stanford press release, Dr. Wang explains the implications of these findings:

“We’ve identified a molecular marker that could allow doctors to diagnose Parkinson’s accurately, early and in a clinically practical way. This marker could be used to assess drug candidates’ capacity to counter the defect and stall the disease’s progression.” 

What is more astounding is that Dr. Wang and her team were also able to identify a compound that is shown to reverse the defect in cells taken from Parkinson’s patients. In an animal model, the compound was able to prevent the death of neurons, which is the underlying problems in the disease.

In their study, Dr. Wang and her team focused on the mitochondria, which churns out energy and is the powerhouse of the cell. Dopaminergic neurons in the brain are some of the body’s hardest working cells, and it is theorized that they start to die off when the mitochondria burns out after constant, high energy production.

Mitochondria spend much of their time attached to a grid of protein “roads” that crisscross cells. Our cells have a technique for clearing “burnt out” mitochondria, but the process involves removing an adaptor molecule called Miro that attaches mitochondria, damaged or healthy, to the grid. 

Dr. Wang’s team previously identified a mitochondrial-clearance defect in Parkinson’s patients’ cells that involved the inability to remove Miro from damaged mitochondria.

In the current study, they obtained skin samples from 83 Parkinson’s patients, Five patients with asymptomatic close relatives considered to be at heightened risk, 22 patients diagnosed with other movement disorders, and 52 healthy control subjects. They extracted fibroblasts, which are cells common in skin tissue, from the samples and subjected them to a stressful process that messes up mitochondria. 

The researchers found the Miro-removal defect in 78 of the 83 Parkinson’s fibroblasts (94%) and in all five of the “high-risk” samples, but not in fibroblasts from the control group or patients with other movement-disorders.

Next, the team was able to screen over 6.8 million molecules and found 11 that would bind to Miro, initiating separation from the mitochondria, are non-toxic, orally available, and able to cross the blood-brain barrier. These 11 compounds were tested in fruit flies and and ultimately one of them, which seems to target Miro exclusively, was tested on fibroblasts from a patient with sporadic Parkinson’s disease. The compound was found to substantially improved Miro clearance in these cells after their exposure to mitochondria-damaging stress.

Dr. Wang is optimistic that clinical trials of the compound or something similar are no more than a few years off.

In the same Stanford press release, Dr. Wang stated that,

“Our hope is that if this compound or a similar one proves nontoxic and efficacious and we can give it, like a statin drug, to people who’ve tested positive for the Miro-removal defect but don’t yet have Parkinson’s symptoms, they’ll never get it.”

The full results of this study were published in the journal Cell Metabolism.

Beige isn’t bland when it comes to solving the obesity epidemic

/ Todd Dubnicoff / Leave a comment

Americans spend over $60 billion a year to lose weight and yet two-thirds (that’s more than 200 million) are considered overweight or obese. Losing weight should be easy: just eat less and exercise more, right? But our body’s metabolism is a very complex thing and appears to fight against our best efforts to shed pounds. A recent analysis of clinical trial data and mathematical modeling suggests that over the long haul, none of the various diet strategies lead to meaningful weight loss. Even the contribution of exercise to weight loss has been called into question.

energy-balance

Lose weight by simply eating less calories than you burn. Easier said than done! (Image credit)

All is not lost. In fact, the fat we carry in our bodies may hold the key to overcoming our obesity woes. A recent CIRM-funded UC Francisco study published in Cell Metabolism finds that harnessing a calorie burning form of fat cells may help guard against the development of obesity.

The Many Hues of Fat
Humans, like other mammals, have two very different types of fat tissue. The more abundant white fat acts to store fat and provides a form of energy to help our body function. An excess of white fat tissue is associated with metabolic diseases including diabetes and obesity. Brown fat tissue, on the other hand, generates heat and is associated with slimness. It was thought that only babies have brown fat which protects them against cold temperatures – they lack the muscle strength for the shivering response – but research in 2009 identified this fat tissue in adults as well.

The UCSF team, led by professor Shingo Kajimura, showed last year that adults actually have so-called beige fat cells that are able to switch from white to brown fat in the presence of colder temperatures and vice versa. This discovery presents the tantalizing potential of promoting weight loss in people by pushing white fat cells toward energy burning brown fat. In that earlier work, the team identified a protein that when inhibited with drugs caused the white fat cells to burn energy like the beige and brown fat. But this effect was short lived and these cells reverted back to the typical features of white fat cells. Kajimura reflected on these previous studies in a university press release:

“Our focus has been on learning to convert white fat into beige fat. Now we’re realizing we also have to think about how to keep it there for longer time.”

In the new study, the team focused on the fact that as beige cells revert back to white cells, their mitochondria – a cell’s energy producing factories – begin to disappear. First author Svetlana Altshuler-Keylin wanted to understand why:

“We knew that the color of brown and beige fat comes from the amount of pigmented mitochondria they contain, so we wondered whether something was going on with the mitochondria when beige fat turns white.”

Stopping cells from eating up too much mitochondria
Examining gene activity as cells went from beige to white implicated a process called autophagy was at play. This house cleaning function of a cell involves the breakdown of its own internal structures that are not functioning properly or aren’t needed. So perhaps stopping the autophagy process from occurring would prevent the energy burning beige cells from eating up their own mitochondria and reverting them back to the energy hoarding white cells.

To test this idea, the team relied on mice lacking genes that play important roles in autophagy. They beefed up their beige fat by subjecting the mice to cold temperatures. But when returned to a normal environment, the mice kept their beige fat and it didn’t convert back to white cells. This change impacted the mice overall health: when place on a fatty diet for two months these mice with the defective autophagy gained less weight. These mice were also able to better regulate blood sugar levels, an indication they there were protected from type 2 diabetes symptoms.

While these results represent very early stage research, Kajimura and his team now have a solid path to travel toward trying to help obese individual burn more calories, especially as they age:

“With age you tend to naturally lose your beige fat, which we think is one of the main drivers of age-related obesity. Your calorie intake stays the same, but you’re not burning as much. Maybe by understanding this process we can help people keep more beige fat, and therefore stay healthier.”

New study says stem cells derived from older people may have more problems than we thought.

/ Kevin McCormack / Leave a comment

heart muscle from iPS

iPS-generated heart muscle cells

Ever since 2006 when Japanese researcher Shinya Yamanaka showed that you could take an adult cell, such as those in your skin, and reprogram it to act like an embryonic stem cell, the scientific world has looked at these induced pluripotent stem (iPS) cells as a potential game changer. They had the ability to convert a person’s own cells into any other kind of cell in the body, potentially offering a way of creating personalized treatments for a wide variety of diseases.

Fears that this reprogramming method might create some cancer-causing genetic mutations seemed to have been eased when two recent studies suggested this approach is relatively safe and unlikely to lead to any tumors in patients. We funded one of those studies and blogged about it.

Reason for caution

But now a new study in the journal Cell Stem Cell  says “not so fast”. The study says the older the person is, the greater the chance that any iPS cells derived from their tissue could contain potentially harmful mutations, but not in the places you would normally think.

A team at Oregon Health and Science University, led by renowned scientist Shoukhrat Mitalipov, took skin and blood samples from a 72-year-old man. The scientists examined the DNA from those samples, then reprogrammed those cells into iPS cells, and examined the DNA from the new stem cells.

Mitalipov-2

Shoukhrat Mitalipov: photo courtesy Oregon Health and Science University

When they looked at the cells collectively the levels of mutations in the new iPS cells appeared to be quite low. But when they looked at individual cells, they noticed a wide variety of mutations in the mitochondria in those cells.

Now, mitochondria play an important role in the life of a cell. They act as a kind of battery, providing the power a cell needs to perform a variety of functions such as signaling and cell growth. But while they are part of the cell, mitochondria have their own genomes. It was here that the researchers found the mutations that raised questions.

Older cells have more problems

Next they repeated the experiment but this time took skin and blood samples from 14 people between the ages of 24 and 72. They found that  older people had more genetic mutations in their mitochondrial DNA that were then transferred to the iPS cells derived from those people. In some cases up to 80 percent of the iPS cell lines generated showed mitochondrial mutations. That’s really important because the greater the amount of mutated mitochondrial DNA in a cell, the more its ability to function is compromised.

In a news release, Mitalipov says this should cause people to pause before using iPS cells derived from an older person for therapeutic purposes:

“Pathogenic mutations in our mitochondrial DNA have long been thought to be a driving force in aging and age-related diseases, though clear evidence was missing. Now with that evidence at hand, we know that we must screen stem cells for mutations or collect them at younger age to ensure their mitochondrial genes are healthy. This foundational knowledge of how cells are damaged in the natural process of aging may help to illuminate the role of mutated mitochondria in degenerative disease.”

To be clear, the researchers are not saying these iPS cells from older people should never be used, only that they need to be carefully screened to ensure they are not seriously damaged before being transplanted into a patient.

A possible solution

Mitalipov suggests a simple way around the problem would be to identify the iPS cell with the best mitochondria, and then use that as the basis for a new cell line that could then be used to create a new therapy.

Taosheng Huang, a researcher at the Mitochondrial Disorders Program at Cincinnati Children’s Hospital Medical Center, is quoted in the news release saying the lesson is clear:

“If you want to use iPS cells in a human, you must check for mutations in the mitochondrial genome. Every single cell can be different. Two cells next to each other could have different mutations or different percentages of mutations.”

Cell survival strategy gives mesenchymal stem cells their “paramedic” properties

/ Todd Dubnicoff / 3 Comments

Electron micrograph of a human mesenchymal stem cells (Credit: Robert M. Hunt)

Electron micrograph of a human mesenchymal stem cells (Image credit: Robert M. Hunt)

A cell for all therapies
Type “mesenchymal stem cells” into the federal online database of registered clinical trials, and you’ll get a sprawling list of 527 trials testing treatments for diabetes, multiple sclerosis as well as diseases of the kidney, lung, and heart, to name just a few. Mesenchymal stem cells (MSCs) have the capacity to specialize into bone, cartilage, muscle and fat cells but their popularity as a therapeutic agent mostly comes from their ability to reduce inflammation and to help repair tissues.

MSCs may be great tools for scientists to fight disease, but what is it about their natural function that make MSCs – as UC Davis researcher Jan Nolta likes to calls them – the body’s “paramedics”? A fascinating study reported yesterday in Nature Communications by scientists at the Florida campus of The Scripps Research Institute (TSRI) and the University of Pittsburgh suggest that it’s a trait the cells gain as a result of their complex cell survival mechanisms.

The TSRI team came to this conclusion by studying how MSCs respond to oxygen-related stress. MSCs reside in the bone marrow where they help maintain and regulate blood stem cells. The bone marrow is naturally a hypoxic, or low oxygen, environment. Growing MSCs in the lab at oxygen levels found in the air we breathe are much higher than what is found in the marrow. This creates oxidative stress in which the excess oxygen leads to unwanted chemical reactions which disrupt a cell’s molecules.

One cell’s trash is another’s treasure
One result of this oxidative stress is damage to the MSCs’ mitochondria, structures responsible for generating the energy needs of a cell. The team found that MSCs package the faulty mitochondria into sacs, or vesicles, which travel to the cell surface to be dumped out of the cell. At this point, another resident of the bone marrow comes into the picture: the macrophage. Previous research has shown that macrophages and MSCs work closely together to maintain the health of the blood stem cells in the bone marrow.

Screen Shot 2015-11-04 at 9.58.48 AM

White arrow shows vesicles (red) carrying mitochondra (green) to the surface of the MSC  and being ingested by a macrophage (round shape in lower half) – (From Fig 2 Nat Commun. 2015 Oct 7;6:8472)

In a high oxygen stress environment, the team observed that MSCs can recruit macrophages to engulf the damaged mitochondria-containing vesicles and repurpose them for their own use. In fact, the researchers measured improved energy production in the macrophages after ingesting the MSCs’ mitochondria. Blocking the transfer of the damaged mitochondria from MSCs to macrophages caused the MSCs to die, confirming that this off-loading of mitochondria to macrophages is critical for MSC survival.

Evolving tricks for cell survival
Macrophages (macro=big; phages=eaters), key players of the immune system and the inflammation response, also rid the body of invading bacteria or damaged cells by devouring them. To avoid being swallowed up by the macrophage while donating its mitochondria, the stressed MSCs have another trick up their sleeve. The research team identified the release of other vesicles from the MSCs that contain molecules called microRNAs which stimulate anti-inflammatory properties in the macrophages. This prevented the macrophages from attacking and eating the MSCs.

And there you have it: as a result of relying on macrophages to survive stressful environments, MSCs appear to have evolved anti-inflammatory activities that turn out to be a handy tool for numerous ongoing and future cell therapy trials.

In a TSRI press release picked up by Newswise, professor Donald Phinney co-leader of study points out the groundbreaking aspect of the study:

Donald G. Phinney

Donald Phinney (photo: TSRI)

“This is the first time anyone has shown how mesenchymal stem cells provide for their own survival by recruiting and then suppressing normal macrophage activity.”

 

 

Mutation Morphs Mitochondria in Models of Parkinson’s Disease, CIRM-Funded Study Finds

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There is no singular cause of Parkinson’s disease, but many—making this disease so difficult to understand and, as a result, treat. But now, researchers at the Buck Institute for Research on Aging have tracked down precisely how a genetic change, or mutation, can lead to a common form of the disease. The results, published last week in the journal Stem Cell Reports, point to new and improved strategies at tackling the underlying processes that lead to Parkinson’s.

Mitochondria from iPSC-derived neurons. On the left is a neuron derived from a healthy individual, while the image on the right shows a neuron derived from someone with the Park2 mutation, the most common mutation in Parkinson's disease (Credit: Akos Gerencser)

Mitochondria from iPSC-derived neurons. On the left is a neuron derived from a healthy individual, while the image on the right shows a neuron derived from someone with the Park2 mutation, the most common mutation in Parkinson’s disease (Credit: Akos Gerencser)

The debilitating symptoms of Parkinson’s—most notably stiffness and tremors that progress over time, making it difficult for patients to walk, write or perform other simple tasks—can in large part be linked to the death of neurons that secrete the hormone dopamine. Studies involving fruit flies in the lab had identified mitochondria, cellular ‘workhorses’ that churn out energy, as a key factor in neuronal death. But this hypothesis had not been tested using human cells.

Now, scientists at the Buck Institute have replicated the process in human cells, with the help of stem cells derived from patients suffering from Parkinson’s, a technique called induced pluripotent stem cell technology, or iPSC technology. These newly developed neurons exactly mimic the disease at the cellular level. This so-called ‘disease in a dish’ is one of the most promising applications of stem cell technology.

“If we can find existing drugs or develop new ones that prevent damage to the mitochondria we would have a potential treatment for PD,” said Dr. Xianmin Zeng, the study’s senior author, in a press release.

And by using this technology, the Buck Institute team confirmed that the same process that occurred in fruit fly cells also occurred in human cells. Specifically, the team found that a particular mutation in these cells, called Park2, altered both the structure and function of mitochondria inside each cell, setting off a chain reaction that leads to the neurons’ inability to produce dopamine and, ultimately, the death of the neuron itself.

This study, which was funded in part by a grant from CIRM, could be critical in the search for a cure for a disease that, as of yet, has none. Current treatment regimens aimed at slowing or reducing symptoms have had some success, but most begin to fail overtime—or come with significant negative side effects. The hope, says Zeng, is that iPSC technology can be the key to fast-tracking promising drugs that can actually target the disease’s underlying causes, and not just their overt symptoms. Hear more from Dr. Xianmin Zeng as she answers your questions about Parkinson’s disease and stem cell research: