(Image caption: In a study of brains from children with autism, neurons in brains from autistic patients did not undergo normal pruning during childhood and adolescence. The images show representative neurons from unaffected brains (left) and brains from autistic patients (right); the spines on the neurons indicate the location of synapses. Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center)

Children with Autism Have Extra Synapses in Brain

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain “pruning” process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC). Because synapses are the points where neurons connect and communicate with each other, the excessive synapses may have profound effects on how the brain functions. The study was published in the August 21 online issue of the journal Neuron.

A drug that restores normal synaptic pruning can improve autistic-like behaviors in mice, the researchers found, even when the drug is given after the behaviors have appeared.

“This is an important finding that could lead to a novel and much-needed therapeutic strategy for autism,” said Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chair of Psychiatry at CUMC and director of New York State Psychiatric Institute, who was not involved in the study.

Although the drug, rapamycin, has side effects that may preclude its use in people with autism, “the fact that we can see changes in behavior suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug,” said the study’s senior investigator, David Sulzer, PhD, professor of neurobiology in the Departments of Psychiatry, Neurology, and Pharmacology at CUMC.

During normal brain development, a burst of synapse formation occurs in infancy, particularly in the cortex, a region involved in autistic behaviors; pruning eliminates about half of these cortical synapses by late adolescence. Synapses are known to be affected by many genes linked to autism, and some researchers have hypothesized that people with autism may have more synapses.

To test this hypothesis, co-author Guomei Tang, PhD, assistant professor of neurology at CUMC, examined brains from children with autism who had died from other causes. Thirteen brains came from children ages two to 9, and thirteen brains came from children ages 13 to 20. Twenty-two brains from children without autism were also examined for comparison.

Dr. Tang measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse.

By late childhood, she found, spine density had dropped by about half in the control brains, but by only 16 percent in the brains from autism patients.

“It’s the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism,” Dr. Sulzer said, “although lower numbers of synapses in some brain areas have been detected in brains from older patients and in mice with autistic-like behaviors.”

Clues to what caused the pruning defect were also found in the patients’ brains; the autistic children’s brain cells were filled with old and damaged parts and were very deficient in a degradation pathway known as “autophagy.” Cells use autophagy (a term from the Greek for self-eating) to degrade their own components.

Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their “self-eating” ability. And without this ability, the brains of the mice were pruned poorly and contained excess synapses. “While people usually think of learning as requiring formation of new synapses, “Dr. Sulzer says, “the removal of inappropriate synapses may be just as important.”

The researchers could restore normal autophagy and synaptic pruning—and reverse autistic-like behaviors in the mice—by administering rapamycin, a drug that inhibits mTOR. The drug was effective even when administered to the mice after they developed the behaviors, suggesting that such an approach may be used to treat patients even after the disorder has been diagnosed.

Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the same processes may occur in children with autism.

“What’s remarkable about the findings,” said Dr. Sulzer, “is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”

Alan Packer, PhD, senior scientist at the Simons Foundation, which funded the research, said the study is an important step forward in understanding what’s happening in the brains of people with autism.

“The current view is that autism is heterogeneous, with potentially hundreds of genes that can contribute. That’s a very wide spectrum, so the goal now is to understand how those hundreds of genes cluster together into a smaller number of pathways; that will give us better clues to potential treatments,” he said.

“The mTOR pathway certainly looks like one of these pathways. It is possible that screening for mTOR and autophagic activity will provide a means to diagnose some features of autism, and normalizing these pathways might help to treat synaptic dysfunction and treat the disease.”

Study Links Enzyme to Alzheimer’s Disease

Unclogging the body’s protein disposal system may improve memory in patients with Alzheimer’s disease (AD), according to a study from scientists at Kyungpook National University in Korea published in The Journal of Experimental Medicine.

In AD, various biochemical functions of brain cells go awry, leading to progressive neuronal damage and eventual memory loss. One example is the cellular disposal system, called autophagy, which is disrupted in patients with AD, causing the accumulation of toxic protein plaques characteristic of the disease. Jae-sung Bae and colleagues had earlier noted that the brains of AD patients have elevated levels of an enzyme called acid sphingomyelinase (ASM), which breaks down cell membrane lipids prevalent in the myelin sheath that coats nerve endings. But whether increased ASM directly contributes to AD (and if so, how) was unclear.

The group now finds that these two defects are linked. In mice with AD-like disease, elevated ASM activity clogged up the autophagy machinery resulting in the accumulation of undigested cellular waste. Reducing levels of ASM restored autophagy, lessened brain pathology, and improved learning and memory in the mice. Provided these results hold true in humans, interfering with ASM activity might prove to be an effective way to slow—and possibly reverse—neurodegeneration in patients with AD.

Using your loaf to fight brain disease

Experts analyse baker’s yeast to discover potential for combatting neurological conditions like Parkinson’s and even cancer

A humble ingredient of bread – baker’s yeast – has provided scientists with remarkable new insights into understanding basic processes likely involved in diseases such as Parkinson’s and cancer.

In a new study published in the prestigious journal PNAS (Proceedings of the National Academy of Science), the team from Germany, Leicester, and Portugal detail a new advance – describing for the first time a key feature in cellular development linked to the onset of these devastating diseases.

The research team is from the University Medical Center Goettingen, University of Leicester, and Instituto de Medicina Molecular, Lisbon, directed by long-time collaborators and senior authors Professor Tiago Outeiro and Dr Flaviano Giorgini.

Professor Outeiro, of the University Medical Center Goettingen, Goettingen and Instituto de Medicina Molecular, Lisbon, said: “This work shows how taking advantage of simple model organisms might help us speed up the discovery of more complex biological processes. Yeast cells are really excellent living test tubes, with a powerful toolbox that enabled us to learn about the underpinnings of complex human disorders.”

Dr Giorgini, of the world-renowned Department of Genetics, at the University of Leicester, added: “We are tremendously excited by our results. The family of proteins under investigation have always been a bit of a “black box”, and a true understanding of what these proteins do at a cellular level - and why they are important - has remained elusive. This work provides a step into this darkness.”

The current research takes advantage of the simplicity and genetic power of the baker’s yeast Saccharomyces cerevisiae to understand basic cellular processes underlying Parkinson’s disease. The team studied a family of proteins in yeast (Hsp31, Hsp32, Hsp33, and Hsp34) which are related to a human protein known as DJ-1. Mutations in the human DJ-1 protein cause early-onset inherited forms of Parkinson’s disease, and alterations in the human protein have been associated with more common forms of Parkinson’s disease as well. In addition, changes in DJ-1 function are also associated with certain forms of cancer.

Claire Bale, Research Communications Manager at Parkinson’s UK, commented: “This important research sheds new light on the root causes of Parkinson’s.

“Although mutations in the DJ-1 gene cause rare inherited forms of the condition, we believe that understanding the role of this crucial protein and how it helps keep nerve cells healthy could be important for developing treatments that can help all people with Parkinson’s. We look forward to hearing the results of future investigations in this emerging new area.”

Professor Outeiro continued: “We reasoned that, by studying the yeast cousins of the human protein we would gain important insight into the function these proteins play, and understand why they may cause disease.

Dr Giorgini added: “Though the human protein DJ-1 has been linked to Parkinson’s disease, its central cellular role is not well understood, and thus it is not clear why mutations in this protein cause this devastating disease. Our study sheds new light on what DJ-1 and related proteins are doing at a cellular level, and may thus ultimately have importance for better understanding Parkinson’s.”

The scientists discovered that the yeast versions of the human protein are important for maintenance of normal lifespan of the yeast cell and are involved in regulation of autophagy – a process which the cell employs to breakdown and recycle damaged cellular components. Lifespan and autophagy are central processes in the context of both Parkinson’s disease and cancer. This work is critical because it provides a precise cellular role for DJ-1 family proteins, which links to some of the molecular functions previously ascribed to these proteins. This work could ultimately provide new insight into the mechanisms that contribute to Parkinson’s and cancer.

Leonor Miller-Fleming, of the Instituto de Medicina Molecular, Lisbon and University of Leicester, said: “Our work is important because it suggests that human DJ-1 may function in a similar manner to the yeast version of this protein. We feel that similar studies should be performed with human DJ-1 in nerve cells, to clarify its function and to see if this contributes to the formation of Parkinson’s disease. Ultimately, the detailed understanding of how these proteins function may enable us to come up with novel strategies to treat Parkinson’s disease, cancer, and other related disorders.”

The collaborators believe the next steps in the research are to better understand the details of how the DJ-1 family of proteins regulates autophagy, and if this applies in human neurons, particularly dopaminergic neurons, which are the nerve cells most sensitive to loss in the Parkinson’s brain. Once the researchers build up on the findings they have now described, they will be in a better position to design novel strategies for therapeutic intervention.

Professor Outeiro explained: “This study highlights the importance of international collaborations and networks, in which different strengths are combined to yield novel insights into science. Importantly, this scientific collaboration is also based upon personal friendship between the two senior authors, which makes science ever more exciting and fun.”

Dr Giorgini added: “In addition, this work was primarily spearheaded by a single PhD student – Leonor Miller-Fleming – who drove the project forward with passion and creativity, showing the importance of promoting, supporting and funding doctoral research.”

Professor Outeiro said: “We were pioneers in the development of the first model of Parkinson’s disease in yeast cells. With this work, we explored the powerful toolbox of yeast cells to learn about DJ-1 proteins, also intimately linked to Parkinson’s disease. We are basically adding pieces to this complicated puzzle, and getting one step closer to understanding the origin of this disorder.”

(Image: © Wikipedia)

Researchers reveal the dual role of brain glycogen

In 2007, in an article published in Nature Neuroscience, scientists at the Institute for Research in Biomedicine (IRB Barcelona) headed by Joan Guinovart, an authority on glycogen metabolism, suggested that in Lafora Disease (LD), a rare and fatal neurodegenerative condition that affects adolescents, neurons die as a result of the accumulation of glycogen—chains of glucose. They went on to propose that this accumulation is the root cause of this disease.

The breakthrough of this paper was two-sided: first, the researchers established a possible cause of LD and therefore were able to point to a plausible therapeutic target, and second, they discovered that neurons have the capacity to store glycogen—an observation that had never been made—and that this accumulation was toxic.

Other reports defended a different theory and upheld that the glycogen deposits were not cause by the neurodegeneration but were a consequence of another, more important, cell imbalance, such as a down deregulation of autophagy—the cell recycling and cleaning programme. In several articles, Guinovart’s “Metabolic engineering and diabetes therapy” group has recently brought to light evidence of the toxicity of glycogen deposits for LD patients, and has now provided irrefutable data.

In an article published at the beginning of February in Human Molecular Genetics, with the research associate Jordi Duran as first author, the scientists show that in LD the accumulation of glycogen directly causes neuronal death and triggers cell imbalances such a decrease in autophagy and synaptic failure. All these alterations lead to the symptoms of LD, such as epilepsy.

Glycogen, a Trojan horse for neurons?

There was still a greater mystery to be solved. Was glycogen synthase truly a Trojan horse for neurons, as apparently established in the article in Nature Neuroscience? That is to say, was the accumulation of glycogen always fatal for cells, thus explaining why their glycogen synthesis machinery is silenced? The inevitable question was then why these cells had such machinery.

In another paper published in Journal of Cerebral Blood Flow & Metabolism, part of the Nature Group, the researchers provided the first evidence that neurons constantly store glycogen but in a different way: accumulating small amounts and using it as quickly as it becomes available. In this regard, the scientists set up new, more sensitive, analytical techniques to confirm that the machinery responsible for glycogen synthesis and degradation existed. In summary, they showed that, in small amounts, glycogen is beneficial for neurons.

“For example, while the liver accumulates glycogen in large amounts and releases it slowly to maintain blood sugar levels, above all when we sleep, neurons synthesize and degrade small amounts of this polysaccharide continuously. They do not use it as an energy store but as a rapid and small, but constant, source of energy,” explains Guinovart, also senior professor at the University of Barcelona (UB).

To observe the action of glycogen, the scientists forced cultured mouse neurons to survive under oxygen depletion. They demonstrated that the first cells to die were those in which the capacity to synthesise glycogen had been removed. The same experiments were performed in collaboration with Marco Milán’s “Development and growth control” group in the in vivo model of the fruit fly Drosophila melanogaster. These tests led to the same conclusions.

The researchers postulated that glycogen is a lifeguard under oxygen depletion, a condition that leads the brains to shut down and that often occurs at birth and in cerebral infarctions in adults, which leads to severe consequences, such a cerebral paralysis.

“It is the first function of glycogen that we have discovered in neurons, but we still have to identify its function in normal conditions and establish how the mechanism works,” says Jordi Duran. Postdoctoral researcher Isabel Saez is the first author of the article out today, which involved the collaboration of ICREA Research Professor Marco Milán’s lab.

The beneficial and toxic roles of brain glycogen are currently the focus of main research lines conducted by Joan Guinovart’s lab.

Toward a Molecular Explanation for Schizophrenia

Surprisingly little is known about schizophrenia. It was only recognized as a medical condition in the past few decades, and its exact causes remain unclear. Since there is no objective test for schizophrenia, its diagnosis is based on an assortment of reported symptoms. The standard treatment, antipsychotic medication, works less than half the time and becomes increasingly ineffective over time.

Now, Prof. Illana Gozes — the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, the director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine, and a member of the Sagol School of Neuroscience at Tel Aviv University — has discovered that an important cell-maintenance process called autophagy is reduced in the brains of schizophrenic patients. The findings, published in Nature’s Molecular Psychiatry, advance the understanding of schizophrenia and could enable the development of new diagnostic tests and drug treatments for the disease.

"We discovered a new pathway that plays a part in schizophrenia," said Prof. Gozes. "By identifying and targeting the proteins known to be involved in the pathway, we may be able to diagnose and treat the disease in new and more effective ways."

Graduate students Avia Merenlender-Wagner, Anna Malishkevich, and Zeev Shemer of TAU, Prof. Brian Dean and colleagues of the University of Melbourne, and Prof. Galila Agam and Joseph Levine of Ben Gurion University of the Negev and Beer Sheva’s Psychiatry Research Center and Mental Health Center collaborated on the research.

Mopping up

Autophagy is like the cell’s housekeeping service, cleaning up unnecessary and dysfunctional cellular components. The process — in which a membrane engulfs and consumes the clutter — is essential to maintaining cellular health. But when autophagy is blocked, it can lead to cell death. Several studies have tentatively linked blocked autophagy to the death of brain cells seen in Alzheimer’s disease.

Brain-cell death also occurs in schizophrenics, so Prof. Gozes and her colleagues set out to see if blocked autophagy could be involved in the progression of that condition as well. They found RNA evidence of decreased levels of the protein beclin 1 in the hippocampus of schizophrenia patients, a brain region central to learning and memory. Beclin 1 is central to initiating autophagy — its deficit suggests that the process is indeed blocked in schizophrenia patients. Developing drugs to boost beclin 1 levels and restart autophagy could offer a new way to treat schizophrenia, the researchers say.

"It is all about balance," said Prof Gozes. "Paucity in beclin 1 may lead to decreased autophagy and enhanced cell death. Our research suggests that normalizing beclin 1 levels in schizophrenia patients could restore balance and prevent harmful brain-cell death."

Next, the researchers looked at protein levels in the blood of schizophrenia patients. They found no difference in beclin 1 levels, suggesting that the deficit is limited to the hippocampus. But the researchers also found increased levels of another protein, activity-dependent neuroprotective protein (ADNP), discovered by Prof. Gozes and shown to be essential for brain formation and function, in the patients’ white blood cells. Previous studies have shown that ADNP is also deregulated in the brains of schizophrenia patients.

The researchers think the body may boost ADNP levels to protect the brain when beclin 1 levels fall and autophagy is derailed. ADNP, then, could potentially serve as a biomarker, allowing schizophrenia to be diagnosed with a simple blood test.

An illuminating discovery

To further explore the involvement of ADNP in autophagy, the researchers ran a biochemical test on the brains of mice. The test showed that ADNP interacts with LC3, another key protein regulating autophagy — an interaction predicted by previous studies. In light of the newfound correlation between autophagy and schizophrenia, they believe that this interaction may constitute part of the mechanism by which ADNP protects the brain.

Prof. Gozes discovered ADNP in 1999 and carved a protein fragment, NAP, from it. NAP mimics the protein nerve cell protecting properties. In follow-up studies Prof. Gozes helped develop the drug candidate davunetide (NAP). In Phase II clinical trials, davunetide (NAP) improved the ability of schizophrenic patients to cope with daily life. A recent collaborative effort by Prof. Gozes and Dr. Sandra Cardoso and Dr. Raquel Esteves showed that NAP improved autophagy in cultures of brain-like cells. The current study further shows that NAP facilitates the interaction of ADNP and LC3, possibly accounting for NAP’s results in schizophrenia patients. The researchers hope NAP will be just the first of their many discoveries to improve understanding and treatment of schizophrenia.

(Image: Shutterstock)

Image: Mice lacking autophagy and with high levels of Aβ (right) have degenerated brain structures compared with normal mice (left).

The benefits of a spotless mind

Alzheimer’s disease is an age-related memory disorder characterized by the accumulation of clumps of the toxic amyloid-β (Aβ) protein fragment in the extracellular space around neurons in the brain. Drugs that help to ‘clean up’ cells by inducing autophagy—the degradation of unnecessary cellular components—are known to lower Aβ levels within cells and have been shown to rescue memory deficits in mice. A team of researchers including Per Nilsson and Takaomi Saido from the RIKEN Brain Science Institute have now found that autophagy also plays an important role in secreting Aβ from the cell into the extracellular space.

The researchers set out to investigate what would happen to extracellular Aβ aggregates, called plaques, when genetic methods were used to eliminate the autophagy process. They started with transgenic mice commonly used as a model for Alzheimer’s disease. These mice have high levels of Aβ and Aβ plaque accumulation in their brains, and display learning and memory deficits. Surprisingly, in genetically engineered variants of these mice lacking autophagy-related gene 7 (Atg7), which is required for normal autophagy, the researchers found fewer extracellular Aβ plaques in the brain; instead, the Aβ seemed to accumulate inside the neurons. Conversely, increasing the expression of the Atg7 protein in neurons grown in cell culture resulted in an increase in the release of Aβ from the cells into the tissue culture medium. The findings suggest that autophagy is required for the secretion of Aβ from neurons into the extracellular environment.

Mice with an elevated expression of Aβ but defective autophagy seemed to have degenerated brain structures, as well as sicker neurons—as defined by their expression of markers of cell death—and worse learning and memory functions than mice with high Aβ expression but normal autophagy. This result indicates that autophagy is important for maintaining normal neuronal function and cognition in Alzheimer’s disease. Moreover, because autophagy lowers Aβ levels within the cell, the researchers deduced that intracellular Aβ may be more toxic than extracellular Aβ with respect to inducing neuronal dysfunction and memory impairment.

The findings suggest that the effectiveness of therapeutic strategies for Alzheimer’s disease may be improved by targeting the elimination of intracellular Aβ deposits rather than extracellular plaques. “Intraneuronal Aβ accumulation is seen in early Alzheimer’s disease in humans, similar to what we found upon autophagy deletion in mice,” explains Nilsson. “Targeting this pool of Aβ may therefore offer a potential treatment for Alzheimer’s disease,” he says.

Cell auto-cleaning mechanism mediates the formation of plaques in Alzheimer’s

Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer’s disease. It might be a potential drug target for the treatment of the disease, concludes new research from the RIKEN Brain Science Institute in Japan. The study sheds light on the metabolism of amyloid beta, and its role in neurodegeneration and memory loss.

In a study published today in the journal Cell Reports, Drs. Per Nilsson, Takaomi Saido and their team show for the first time using transgenic mice that a lack of autophagy in neurons prevents the secretion of amyloid beta and the formation of amyloid beta plaques in the brain. The study also reveals that an accumulation of amyloid beta inside neurons is toxic for the cells.

Alzheimer’s disease, the most common form of dementia, affects nearly 36 million people worldwide, and this number is set to double over the next 20 years. However, the causes of the disease are not well understood and no disease-modifying treatment is available today.

Patients with Alzheimer’s disease have elevated levels of the peptide amyloid beta in their brain and amyloid beta plaques form outside their neurons. This accumulation of amyloid beta causes the neurons to die, but until now the underlying mechanism remained a mystery. And whether the elevated levels of the peptide inside or outside the cells are to blame was unknown.

Autophagy is a cellular cleaning mechanism that normally clears any protein aggregates or other ‘trash’ within the cells, but that is somewhat disturbed in Alzheimer’s patients.

To investigate the role of autophagy in amyloid beta metabolism, Nilsson et al. deleted an important gene for autophagy, Atg7, in a mouse model of Alzheimer’s disease. Contrary to what they were expecting, their results showed that a complete lack of autophagy within neurons prevents the formation of amyloid beta plaque around/outside the cells. Instead, the peptide accumulates inside the neurons, where it causes neuronal death, which in turn leads to memory loss.

“Our study explains how amyloid beta is secreted from the neurons, via autophagy, which wasn’t well understood,” comments Dr Nilsson. “To control amyloid beta metabolism including its secretion is a key to control the disease. Autophagy might therefore be a potential drug target for the treatment of Alzheimer’s disease,” he adds.

Spring cleaning in your brain: U-M stem cell research shows how important it is

Deep inside your brain, a legion of stem cells lies ready to turn into new brain and nerve cells whenever and wherever you need them most. While they wait, they keep themselves in a state of perpetual readiness – poised to become any type of nerve cell you might need as your cells age or get damaged.

Now, new research from scientists at the University of Michigan Medical School reveals a key way they do this: through a type of internal “spring cleaning” that both clears out garbage within the cells, and keeps them in their stem-cell state.

In a paper published online in Nature Neuroscience, the U-M team shows that a particular protein, called FIP200, governs this cleaning process in neural stem cells in mice. Without FIP200, these crucial stem cells suffer damage from their own waste products — and their ability to turn into other types of cells diminishes.

It is the first time that this cellular self-cleaning process, called autophagy, has been shown to be important to neural stem cells.

The findings may help explain why aging brains and nervous systems are more prone to disease or permanent damage, as a slowing rate of self-cleaning autophagy hampers the body’s ability to deploy stem cells to replace damaged or diseased cells. If the findings translate from mice to humans, the research could open up new avenues to prevention or treatment of neurological conditions.

In a related review article just published online in the journal Autophagy, the lead U-M scientist and colleagues from around the world discuss the growing evidence that autophagy is crucial to many types of tissue stem cells and embryonic stem cells as well as cancer stem cells.

As stem cell-based treatments continue to develop, the authors say, it will be increasingly important to understand the role of autophagy in preserving stem cells’ health and ability to become different types of cells.

“The process of generating new neurons from neural stem cells, and the importance of that process, is pretty well understood, but the mechanism at the molecular level has not been clear,” says Jun-Lin Guan, Ph.D., the senior author of the FIP200 paper and the organizing author of the autophagy and stem cells review article. “Here, we show that autophagy is crucial for maintenance of neural stem cells and differentiation, and show the mechanism by which it happens.”

Through autophagy, he says, neural stem cells can regulate levels of reactive oxygen species – sometimes known as free radicals – that can build up in the low-oxygen environment of the brain regions where neural stem cells reside. Abnormally higher levels of ROS can cause neural stem cells to start differentiating.

Guan is a professor in the Molecular Medicine & Genetics division of the U-M Department of Internal Medicine, and in the Department of Cell & Developmental Biology.

A long path to discovery

The new discovery, made after 15 years of research with funding from the National Institutes of Health, shows the importance of investment in lab science – and the role of serendipity in research.

Guan has been studying the role of FIP200 — whose full name is focal adhesion kinase family interacting protein of 200 kD – in cellular biology for more than a decade. Though he and his team knew it was important to cellular activity, they didn’t have a particular disease connection in mind. Together with colleagues in Japan, they did demonstrate its importance to autophagy – a process whose importance to disease research continues to grow as scientists learn more about it.

Several years ago, Guan’s team stumbled upon clues that FIP200 might be important in neural stem cells when studying an entirely different phenomenon. They were using FIP200-less mice as comparisons in a study, when an observant postdoctoral fellow noticed that the mice experienced rapid shrinkage of the brain regions where neural stem cells reside.

“That effect was more interesting than what we were actually intending to study,” says Guan, as it suggested that without FIP200, something was causing damage to the home of neural stem cells that normally replace nerve cells during injury or aging.

In 2010, they worked with other U-M scientists to show FIP200’s importance to another type of stem cell, those that generate blood cells. In that case, deleting the gene that encodes FIP200 leads to an increased proliferation and ultimate depletion of such cells, called hematopoietic stem cells.

But with neural stem cells, they report in the new paper, deleting the FIP200 gene led neural stem cells to die and ROS levels to rise. Only by giving the mice the antioxidant n-acetylcysteine could the scientists counteract the effects.

“It’s clear that autophagy is going to be important in various types of stem cells,” says Guan, pointing to the new paper in Autophagy that lays out what’s currently known about the process in hematopoietic, neural, cancer, cardiac and mesenchymal (bone and connective tissue) stem cells.

Guan’s own research is now exploring the downstream effects of defects in neural stem cell autophagy – for instance, how communication between neural stem cells and their niches suffers. The team is also looking at the role of autophagy in breast cancer stem cells, because of intriguing findings about the impact of FIP200 deletion on the activity of the p53 tumor suppressor gene, which is important in breast and other types of cancer. In addition, they will study the importance of p53 and p62, another key protein component for autophagy, to neural stem cell self-renewal and differentiation, in relation to FIP200.