University of South Florida Health neuroscientists discover a defect early in autophagy that may help develop SSH1 inhibitors to treat Alzheimer’s and other neurodegenerative diseases

When the physiological process of autophagy runs smoothly, cellular waste is routinely collected for disposal so it does not pile up like garbage at the curbside.

TAMPA, Fla (Oct. 12, 2020) — In a healthy brain, the multistep waste clearance process known as autophagy routinely removes and degrades damaged cell components – including malformed proteins like tau and toxic mitochondria. This cellular debris would otherwise pile up like uncollected trash to drive the death of brain cells (neurons), ultimately destroying cognitive abilities like thinking, remembering and reasoning in patients with Alzheimer’s and certain other neurodegenerative diseases.

The protein p62, a selective autophagy cargo receptor, plays a major role in clearing misfolded tau proteins and dysfunctional mitochondria, the energy powerhouse in all cells including neurons. Through autophagy (meaning “self-eating” in Greek) old or broken cellular material is ultimately digested and recycled in lysosomes, membrane-bound structures that work like mini-waste management plants.

Now, neuroscientists at the University of South Florida Health (USF Health) Byrd Alzheimer’s Center report for the first time that the protein phosphatase Slingshot-1, or SSH1 for short, disrupts p62’s ability to function as an efficient “garbage collector” and thereby impairs the disposal of both damaged tau and mitochondria leaking toxins. In a preclinical study, the researchers showed that SSH1’s influence in halting p62-mediated protective clearance of tau was separate from SSH1’s role in activating cofilin, an enzyme that plays an essential part in worsening tau pathology.

Their findings were published Oct. 12  in Autophagy.

David Kang, PhD, professor of molecular medicine at the USF Health Byrd Alzheimer’s Center, was senior author of the study published in Autophagy.

First author Cenxiao Fang, MD, PhD

“Slingshot-1 is an important player in regulating the levels of tau and neurotoxic mitochondria, so it’s important to understand exactly what’s going wrong when they accumulate in the brain,” said the paper’s senior author David Kang, PhD, professor of molecular medicine at the USF Health Morsani College of Medicine, who holds the Fleming Endowed Chair in Alzheimer’s Disease and serves as the director of basic research at the Byrd Alzheimer’s Center. “This study provides more insight into a defect stemming from the p62 pathway, which will help us develop SSH1 inhibitors (drugs) to stop or slow Alzheimer’s disease and related neurodegenerative disorders.”

First enzyme leading to p62 deactivation

At the start of their study, Dr. Kang’s team, including first author and doctoral student Cenxiao (Catherine) Fang, MD, already knew that, in the case of clearing bad mitochondria (known as mitophagy), the enzyme TBK1 transiently adds phosphate to p62. Phosphate is specifically added at the site of amino acid 403 (SER403), which activates p62. However, no scientist had yet discovered what enzyme removes phosphate from p62, known as dephosphorylation. Tightly controlled phosphorylation is needed to strike a balance in p62 activation, an early step key in priming the cargo receptor’s ability to recognize and collect chunks of cellular waste labelled as “garbage” by a ubiquitin tag. Put simply, when autophagy works well, ubiquitinated tau and ubiquitinated mitochondria are selectively targeted for collection and then delivered for destruction and recycling by autophagosomes (the garbage trucks in this dynamic process). But, garbage collector p62 doesn’t touch the cell’s healthy (untagged) proteins and organelles.

In a series of gene deactivation and overexpression experiments using human cell lines, primary neurons, and a mouse model of tauopathy, Dr. Kang’s team discovered SSH1, acting specifically on SER403, as the first enzyme to remove this key phosphate off p62, causing p62 deactivation.

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“When something shifts out of balance, like overactivation of Slingshot-1 by Alzheimer’s-related protein Aβ for example, then SSH1 starts to remove the phosphate off the garbage collector p62, essentially relaying the message ‘stop, don’t do your job.’  That leads to bad consequences like accumulation of damaged tau proteins and toxic mitochondria,” Dr. Kang said. “If we can bring phosphorylation regulation back into balance through inhibitors that dampen overactive Slingshot-1, we can increase p62’s normal activity in removing the toxic garbage.”

Learning more from a surprising result

This latest study builds upon previous USF Health research showing that Aβ-activated cofilin, which occurs through SSH1, essentially kicks tau from the microtubules providing structural support to neurons, thereby boosting the build-up of tau tangles inside dying nerve cells. In the displacement process, cofilin gets transported to mitochondria and damage to the energy-producing mitochondria ensues.

Following up on that collateral cofilin-triggered damage, Dr. Kang’s team expected to find a widespread mitophagy upon SSH1 expression — a typical response to clear out the damaged mitochondria.

“However, we found the opposite of what we expected. That is, SSHI expression suppressed the mitophagy response, which meant that Slingshot-1 was suppressing mitophagy through another mechanism,” Dr. Kang said. “That mechanism turned out to be inactivation of p62, which occurs simultaneously with cofilin activation.”

The researchers showed that two major and entirely separate signaling pathways implicated in tau pathology – one for p62 and another for cofilin – are both regulated by the same enzyme, SSH1.

“In addition to the SSH1-cofilin activation pathway in promoting tau displacement from microtubules, this study highlights the divergent SSH1-p62 inhibitory pathway in impairing autophagic clearance of misfolded tau,” the study authors report.

Cellular autophagy illustration showing the fusion of a lysosome (upper left) with an autophagosome.

The USF Health study was supported by grants from the NIH’s National Institute on Aging and National Institute of Neurological Disorders and Stroke, the U.S. Department of Veterans Affairs, and the Florida Department of Health. This research represented a major part of the doctoral thesis of the first author Cenxiao Fang, MD, PhD, who recently received her PhD degree from USF and is now a postdoctoral scholar at the University of Minnesota.

University of South Florida study suggests a new approach to inhibit the buildup of brain-damaging tau tangles associated with FTLD, Alzheimer’s disease and related dementias

TAMPA, Fla. (Feb. 18, 2020) — The protein β-arrestin2 increases the accumulation of neurotoxic tau tangles, a cause of several forms of dementia, by interfering with removal of excess tau from the brain, a new study by the University of South Florida Health (USF Health) Morsani College of Medicine found.

A beta-arrestin2 oligomer (foreground) shown within a nerve cell (background). Oligomerized beta-arrestin2 plays a central role in impairing tau clearance and the development of tau aggregates (magenta) in frontotemporal lobe degeneration and Alzheimer’s disease. | Image courtesy of artist Cynthia Greco and Eric Lewandowski (beta-arrestin2 protein modeling)

The USF Health researchers discovered that a form of the protein comprised of multiple β-arrestin2 molecules, known as oligomerized β-arrestin2, disrupts the protective clearance process normally ridding cells of malformed proteins like disease-causing tau. Monomeric β-arrestin2, the protein’s single-molecule form, does not impair this cellular toxic waste disposal process known as autophagy.

Their findings were first published Feb. 18 in the Proceedings of the National Academy of Science (PNAS).

The study focused on frontotemporal lobar degeneration (FTLD), also called frontotemporal dementia — second only to Alzheimer’s disease as the leading cause of dementia. This aggressive, typically earlier onset dementia (ages 45-65) is characterized by atrophy of the front or side regions of the brain, or both. Like Alzheimer’s disease, FTLD displays an accumulation of tau, and has no specific treatment or cure.

“Our research could lead to a new strategy to block tau pathology in FTLD, Alzheimer’s disease and other related dementias, which ultimately destroys cognitive abilities such as reasoning, behavior, language, and memory,” said the paper’s lead author JungA (Alexa) Woo, PhD, an assistant professor of molecular pharmacology and physiology and an investigator at the USF Health Byrd Alzheimer’s Center.

“It has always been puzzling why the brain cannot clear accumulating tau” said Stephen B. Liggett, MD, senior author and professor of medicine and medical engineering at the USF Health Morsani College of Medicine. “It appears that an ‘incidental interaction’ between β-arrestin2 and the tau clearance mechanism occurs, leading to these dementias. β-arrestin2 itself is not harmful, but this unanticipated interplay appears to be the basis for this mystery.”

The USF Health research team included, from left: Stephen Liggett, MD, senior author; David Kang, PhD, coauthor; and JungA (Alexa) Woo, PhD, lead author. | Photo by Freddie Coleman

“This study identifies beta-arrestin2 as a key culprit in the progressive accumulation of tau in brains of dementia patients,” said coauthor David Kang, PhD, professor of molecular medicine and director of basic research for the Byrd Alzheimer’s Center. “It also clearly illustrates an innovative proof-of-concept strategy to therapeutically reduce pathological tau by specifically targeting beta-arrestin oligomerization.”

The two primary hallmarks of Alzheimer’s disease are clumps of sticky amyloid-beta (Aβ) protein fragments known as amyloid plaques and neuron-choking tangles of a protein called tau. Abnormal accumulations of both proteins are needed to drive the death of brain cells, or neurons, in Alzheimer’s, although the tau accumulations now appear to correlate better with cognitive dysfunction than Aβ, and drugs targeting Ab have been disappointing as a treatment. Aβ aggregation is absent in the FTLD brain, where the key feature of neurodegeneration appears to be excessive tau accumulation, known as tauopathy. The resulting neurofibrillary tangles — twisted fibers laden with tau — destroy synaptic communication between neurons, eventually killing the brain cells.

“Studying FTLD gave us that window to study a key feature of both types of dementias, without the confusion of any Aβ component,” Dr. Woo said.

Monomeric β-arrestin2 is mostly known for its ability to regulate receptors, molecules on the cell that are responsible for hormone and neurotransmitter signaling. β-arrestin2 can also form multiple interconnecting units, called oligomers. The function of β-arrestin2 oligomers is not well understood.

The monomeric form was the basis for the laboratory’s initial studies examining tau and its relationship with neurotransmission and receptors, “but we soon became transfixed on these oligomers of β-arrestin2,” Dr Woo said.

Neurofibrillary tangles laden with tau (stained red) destroy synaptic communication between neurons, eventually killing the brain cells. This tau pathology is a feature of frontotemporal dementia, Alzheimer’s disease and several other dementias. | Image courtesy of David Kang

Among the researchers’ findings reported in PNAS:

– Both in cells and in mice with elevated tau, β-arrestin2 levels are increased. Furthermore, when β-arrestin 2 is overexpressed, tau levels increase, suggesting a maladaptive feedback cycle that exacerbates disease-causing tau.

–  Genetically reducing β-arrestin2 lessens tauopathy, synaptic dysfunction, and the loss of nerve cells and their connections in the brain. For this experiment researchers crossed a mouse model of early tauopathy with genetically modified mice in which the β–arrestin2 gene was inactivated, or knocked out.

– Oligomerized β-arrestin2 — but not the protein’s monomeric form – increases tau.  The researchers blocked β-arrestin-2 molecules from binding together to create oligeromized forms of the protein. They demonstrated that pathogenic tau significantly decreased when β-arrestin2 oligomers are converted to monomers

– Oligomerized β-arrestin2 increases tau by impeding the ability of cargo protein p62 to help selectively degrade excess tau in the brain. In essence, this reduces the efficiency of the autophagy process needed to clear toxic tau, so tau “clogs up” the neurons.

– Blocking of β-arrestin2 oligomerization suppresses disease-causing tau in a mouse model that develops human tauopathy with signs of dementia.

Above: Control nerve cells (green), in which oligomerized beta-arrestin-2 contributes to the accumulation of disease-causing tau (magenta). Below: When the neurons are transduced with b-arrestin2 oligomerization blocking viruses, tau pathology is dramatically reduced. | Images appearing in PNAS (Fig 6D) courtesy of Alexa Woo

“We also noted that decreasing β-arrestin2 by gene therapy had no apparent side effects, but such a reduction was enough to open the tau clearance mechanism to full throttle, erasing the tau tangles like an eraser,” Dr. Liggett said. “This is something the field has been looking for — an intervention that does no harm and reverses the disease.”

“Based on our findings, the effects of inhibiting β-arrestin2 oligomerization would be expected to not only inhibit the development of new tau tangles, but also to clear existing tau accumulations due to the mechanism of enhancing tau clearance,” the paper’s authors conclude.

The work is consistent with a new treatment strategy that could be preventive for those at risk or with mild cognitive impairment, and also for those with overt dementias caused by tau, by decreasing the existing tau tangles.

The study was supported in part by grants from the National Institutes of Health, National Institute on Aging.

His team searches beyond the hallmark Alzheimer’s disease proteins for alternative treatments

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In his laboratory at the USF Health Byrd Alzheimer’s Center, neuroscientist David Kang, PhD, focuses on how different types of proteins damage the brain when they accumulate there. In the case of Alzheimer’s disease, decades of good science has zeroed in on amyloid and tau, as the two types of hallmark proteins driving the disease process that ultimately kills brain cells.

Dr. Kang and his team investigate molecular pathways leading to the formation large, sticky amyloid plaques between brain cells, and to the tau neurofibrillary tangles inside brain cells –including the interplay between the two proteins. But, he is quick to point out that amyloid and tau are “not the full story” in the quest to understand how normally aging brains go bad.

“Our goal is to understand as much of the entire Alzheimer’s disease process as possible and then target specific molecules that are either overactive or underactive, which is part of the drug discovery program we’re working on,” said Dr. Kang, professor of molecular medicine and director of basic research for the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Neuroscientist David Kang, PhD, (third from left)  stands with his team in his laboratory at the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Attacking dementia from different angles 

Dr. Kang’s group takes a multifaceted approach to studying the biological brain changes that impair thinking and memory in people with Alzheimer’s, the most common type of dementia, as well as Lewy body, vascular and frontotemporal dementias.

That includes examining how damaged mitochondria, the energy-producing power plants of the cell, contribute to pathology in all neurodegenerative diseases. “Sick mitochondria leak a lot of toxins that do widespread damage to neurons and other cells,” Dr. Kang said.

Dr. Kang’s team was the first to identify how mutations of a gene, called CHCHD10, which contributes to both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), cause both mitochondrial dysfunction and protein pathology called TDP-43. Their findings on the newly identified mitochondrial link to both neurodegenerative diseases were published in Nature Communications in 2017.

The role of selective degradation in ridding cells of abnormal proteins, old or damaged organelles (including mitochondria) and other debris is another key line of research pursued by Dr. Kang and colleagues.

A single stained nerve cell | Microscopic image courtesy of Kang lab

“We believe something more fundamental is going wrong in the brain during the aging process to tip the balance toward Alzheimer’s disease – beyond what we call proteinopathy” or deposits of malformed proteins like toxic amyloid and tau, said Dr. Kang, whose work is bolstered by nearly $8 million in grant funding from the National Institutes of Health (NIH), the Veterans Administration (VA merit awards) and the Florida Department of Health.

“I think one of the fundamental things happening is that the (cellular) plumbing system isn’t working to clear out all the accumulating junk,” he said. “That’s why we’re looking at the protective clearance mechanisms (autophagy and mitophagy) that would normally quickly remove misfolded proteins and dysfunctional mitochondria.”

Unfortunately, pharmaceutical trials to date have yielded no effective treatments for Alzheimer’s disease, the sixth leading cause of death in the U.S.  Most clinical studies have centered on developing medications to block or destroy the amyloid protein plaque formation, and a few have targeted the tau-containing neurofibrillary tangles. The five Alzheimer’s drugs currently available may provide temporary relief of symptoms, such as memory loss and confusion. But, they do not prevent or delay the mind-robbing disease as toxic proteins continue to build up and dismantle the brain’s communication network.

Lesson learned: The critical importance of intervening earlier

Some scientists argue that the “amyloid hypothesis” approach is not working. Dr. Kang is among those who maintain that amyloid plays a key role in initiating the disease process that leads to brain atrophy in Alzheimer’s – but that amyloid accumulation happens very early, as much as 10 to 20 years before people experience memory problems or other signs of dementia.

Early detection and treatment are key, Dr. Kang says, because as protein plaques and other lesions continue to accumulate in the brain, reversing the damage may not be possible.

“One reason we’ve been disappointed in the clinical trials is because so far they have primarily targeted patients who are already symptomatic,” Dr. Kang said. “Over the last decade we’ve learned that by the time someone is diagnosed with early Alzheimer’s disease, or even mild cognitive impairment, the brain has degenerated a lot. And once those nerve cells are gone they do not, for the most part, regenerate… The amyloid cascade has run its course.”

As protein plaques and other lesions continue to accumulate, becoming apparent with MRI imaging, reversing the damage may not be possible.  So, for anti-amyloid therapies – or even those targeting downstream tau – to work, patients at risk of Alzheimer’s need to be identified and treated very early, Dr. Kang said.

USF Health is recruiting healthy older adults with no signs of memory problems for a few prevention trials. A pair of Generation Program studies will test the effectiveness of investigational anti-Alzheimer’s drugs on those at high genetic risk for the disease before symptoms start. And, the NIH-sponsored Preventing Alzheimer’s with Cognitive Training (PACT) study is examining whether a specific type of computerized brain training can reduce the risk of mild cognitive impairment and dementias like Alzheimer’s disease in those age 65 and older.

To accelerate early intervention initiatives, more definitive tests are needed to pinpoint biomarkers that will predict Alzheimer’s disease development in genetically susceptible people. Dr. Kang is hopeful about the prospects.  His own team investigates how exosomes, in particular the lipid vesicles that shuttle proteins and other molecules from the brain into the circulating bloodstream, might be isolated and used to detect people at risk of proteinopathy.

“I think within the next five years, some type of diagnostic blood test will be available that can accurately identify people with early Alzheimer’s brain pathology, but not yet experiencing symptoms,” he said.

Graduate research assistant Yan Yan, a member of Dr. Kang’s research team, works at a cell culture hood.

Searching for alternative treatment targets

Meanwhile, Dr. Kang’s laboratory continues searching for other treatment targets in addition to amyloid and tau — including the enzyme SSH1, which regulates the internal infrastructure of nerve cells, called the actin cytoskeleton. SSHI, also known as slingshot, is needed for amyloid activation of cofilin, a protein identified by the USF Health neuroscientists in a recent study published in Communications Biology as a possible early culprit in the tauopathy process.

“Cofilin is overactive in the brains of Alzheimer’s patients so if we can inhibit cofilin by targeting slingshot, it may lead to a promising treatment,” Dr. Kang said.

Ultimately, as with other complex chronic diseases, Alzheimer’s may not be eliminated by a single silver-bullet cure.  Rather, Dr. Kang said, a combination of approaches will likely be needed to successfully combat the neurodegenerative disorder, which afflicts 5.8 million Americans.

“I think prevention through healthy living is definitely key, because brain aging is modifiable based on things like your diet as well as physical activity and brain exercises,” he said.  “Also, we need to focus on earlier diagnosis, before people become symptomatic, and develop next-generation drugs that can attack the disease on multiple fronts.”

Xingyu Zhao, PhD, a research associate in the Department of Molecular Medicine, is among the scientists in Dr. Kang’s laboratory studying the basic biology of the aging brain.

Fascinated by how the brain works — and malfunctions

Dr. Kang came to USF Health in 2012 after nearly 20 years as a brain researcher at the University of California San Diego, where he earned M.S. and PhD degrees in neurosciences and completed NIH National Research Service Award fellowships in the neuroplasticity of aging.

As an undergraduate Dr. Kang switched from studying engineering to a dual major in science/psychology. He began focusing on neurosciences in graduate school, he said, because tackling how the brain works and malfunctions was fascinating and always challenged him.

“With every small step forward, we learn something else about the basic biology of the aging brain,” said Dr. Kang, “It’s not just helpful in discovering what therapeutic approaches may work best against Alzheimer’s disease – we’re also learning more about other neurodegenerative conditions affecting the brain.”

In addition to leading day-to-day research operations at the Byrd Center and helping to recruit new Alzheimer’s investigators, Dr. Kang holds the Mary and Louis Fleming Endowed Chair in Alzheimer’s Research and serves as a research neurobiologist at the James A. Haley Veterans Haley Veterans’ Hospital.

He has authored more than 50 peer-reviewed journal articles on brain aging and Alzheimer’s disease research. A member of the NIH Clinical Neuroscience and Neurodegeneration Study Section since 2016, he has served on multiple national and international editorial boards, scientific panels and advisory boards.

Dr. Kang sits next to a computer monitor depicting stained microscopic images — a single neuron (far left) and the two hallmark pathological proteins for Alzheimer’s disease, tau tangles (center) and amyloid plaques (right).

Some things you may not know about Dr. Kang

• His parents were Presbyterian missionaries in Africa, so he spent nine years of his early life (third through 10^th grade) in Nigeria.
• Dr. Kang practices intermittent fasting, often forgoing breakfast and eating only within an 8-hour window. Animal studies indicate the practice may contribute to lifespan and brain health by improving cellular repair through the process of autophagy, he said. “Autophagy really kicks your cells’ plumbing system into gear to clear out all the waste.”

-Video and photos by Allison Long, USF Health Communications and Marketing

USF Health study links Aβ-activated enzyme cofilin with the toxic tau tangles in major neurodegenerative disorders like Alzheimer’s disease

Neurofibrillary tau tangles (stained red) are one of the two major brain lesions of Alzheimer’s disease. Blue fluorescent stain (DAPI) depicts the nerve cell nuclei.

TAMPA, Fla. — The two primary hallmarks of Alzheimer’s disease are clumps of sticky amyloid-beta (Aβ) protein fragments known as amyloid plaques and neurofibrillary tangles of a protein called tau.  Abnormal accumulations of both proteins are needed to drive the death of brain cells, or neurons. But scientists still have a lot to learn about how amyloid impacts tau to promote widespread neurotoxicity, which destroys cognitive abilities like thinking, remembering and reasoning in patients with Alzheimer’s.

While investigating the molecular relationship between amyloid and tau, University of South Florida neuroscientists discovered that the Aβ-activated enzyme cofilin plays an essential intermediary role in worsening tau pathology.

Their latest preclinical study was reported March 22, 2019 in Communications Biology.

The research introduces a new twist on the traditional view that adding phosphates to tau (known as phosphorylation) is the most important early event in tau’s detachment from brain cell-supporting microtubules and its subsequent build-up into neurofibrillary tangles. These toxic tau tangles disrupt brain cells’ ability to communicate, eventually killing them.

David Kang, PhD, director of basic research at the Byrd Alzheimer’s Center, USF Health Neuroscience Institute, was senior author of the Communications Biology paper.

“We identified for the first time that cofilin binds to microtubules at the expense of tau – essentially kicking tau off the microtubules and interfering with tau-induced microtubule assembly. And that promotes tauopathy, the aggregation of tau seen in neurofibrillary tangles,” said senior author David Kang, PhD, a professor of molecular medicine at the USF Health Morsani College of Medicine and director of basic research at Byrd Alzheimer’s Center, USF Health Neuroscience Institute.

Dr. Kang also holds the Fleming Endowed Chair in Alzheimer’s Research at USF Health and is a biological scientist at James A. Haley Veterans’ Administration Hospital. Alexa Woo, PhD, assistant professor of molecular pharmacology and physiology and member of the Byrd Alzheimer’s Center, was the study’s lead author.

The study builds upon previous work at USF Health showing that Aβ activates cofilin through a protein known as Slingshot, or SSH1. Since both cofilin and tau appear to be required for Aβ neurotoxicity, in this paper the researchers probed the potential link between tau and cofilin.

The microtubules that provide structural support inside neurons were at the core of their series of experiments.

Alexa Woo, PhD, an assistant professor of molecular pharmacology and physiology at the USF Health Morsani College of Medicine, was the paper’s lead author.

Without microtubules, axons and dendrites could not assemble and maintain the elaborate, rapidly changing shapes needed for neural network communication, or signaling. Microtubules also function as highly active railways, transporting proteins, energy-producing mitochondria, organelles and other materials from the body of the brain cell to distant parts connecting it to other cells. Tau molecules are like the railroad track ties that stabilize and hold train rails (microtubules) in place.

Using a mouse model for early-stage tauopathy, Dr. Kang and his colleagues showed that Aβ-activated cofilin promotes tauopathy by displacing the tau molecules directly binding to microtubules, destabilizes microtubule dynamics, and disrupts synaptic function (neuron signaling) — all key factors in Alzheimer’s disease progression. Unactivated cofilin did not.

The researchers also demonstrated that genetically reducing cofilin helped prevent the tau aggregation leading to Alzheimer’s-like brain damage in mice.

An amyloid plaque (stained red), one of the two major brain lesions of Alzheimer’s disease, is shown here with the Aβ-activated enzyme cofilin (green) and nerve cell nuclei (blue).

“Our data suggests that cofilin kicks tau off the microtubules, a process that possibly begins even before tau phosphorylation,” Dr. Kang said. “That’s a bit of a reconfiguration of the canonical model of how the pathway leading to tauopathy works.”

Since cofilin activation is largely regulated by SSH1, an enzyme also activated by Aβ, the researchers propose that inhibiting SSH1 represents a new target for treating Alzheimer’s disease or other tauopathies. Dr. Kang’s laboratory is working with James Leahy, PhD, a USF professor of chemistry, and Yu Chen, PhD, a USF Health professor of molecular medicine, on refining several SSH1 inhibitors that show preclinical promise as drug candidates.

The research described in this Communications Biology paper was supported by grants from the VA, the NIH National Institute on Aging, and the Florida Department of Health.

Schematic of activated cofilin in tauopathy, which leads to pathological brain changes in people with Alzheimer’s disease and other major neurodegenerative disorders | Courtesy of Alexa Woo

-Photos by Allison Long, USF Health Communications and Marketing

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two rare neurodegenerative diseases also considered as spectrum disorders, affect thousands of Americans every year.

ALS, a condition that effects nerves and muscles, and FTD, a disorder that causes changes in behavior and personality, language, motor skills and function, are associated with one another due to a common genetic mutation in multiple genes.

David Kang, PhD, professor of molecular medicine, in his laboratory at the USF Health Byrd Alzheimer’s Institute. He was the study’s lead author. 

However, researchers did not know exactly why that happened until a new research breakthrough at University of South Florida Health in Tampa, Florida.

A group of USF Health researchers found that a mutated ALS and FTD gene is pathologically linked to mitochondria dysfunction and TDP-43 pathology – causing problems for people affected by either disease.

The results of this study were published in Nature Communications Journal.

The study’s lead investigator David Kang, PhD, professor of molecular medicine and researcher at the USF Health Byrd Alzheimer’s Institute, said that this is a very important pathological link for ALS and FTD.

“Mutations in the ALS and FTD gene, called CHCHD10, are instigating dysfunction in the mitochondria, the cell powerhouse plants that produce the majority of the energy in the human body,” Dr. Kang said. “This gene allows TDP-43, a protein that’s part of the nuclear function, to exit the nucleus to get into the cytoplasm or cell body and cause TDP 43-pathology – which is relatively specific to ALS and FTD.”

While many genes cause ALS and FTD, this gene is the first one that’s been linked to mitochondria, Dr. Kang said. Dr. Kang and his team of researchers have worked on this study for two years, supported by grants from the Veterans Administration, National Institutes of Health and Florida Department of Health.

Dr. Kang (second from right) with some members of his research team. From left: JungA (Alexa) Woo, PhD, assistant professor; Courtney Trotter, graduate research assistant; and Tian Lu, PhD, postdoctoral research scholar, Department of Molecular Medicine, USF Health Morsani College of Medicine.

To come up with the results, the USF Health researchers studied worms, mammalian cell lines, primary neurons and mouse brains. The models allowed them to prove that the mutated gene is very important to the mitochondrial function, which the human body needs.

“We took the human gene, CHCHD10, and we put it into worms with a short life-span,” Dr. Kang said. “We used worms who lacked the CHCHD10 gene and had dysfunctional mitochondria, which, as a result, had motor problems and could not move properly. What happened was that the normal human gene helped the worms live longer – completely rescuing their abnormalities and restoring their mitochondria function and movement. However, when we put the single mutated gene that causes ALS and FTD into the worm, it did not rescue at all. They were still completely dysfunctional.”

The USF Health research team suggests that these results are critical to ALS and FTD research. This was the first study to show that the normal gene increases mitochondria function and the mutant gene increases mitochondria dysfunction. The normal gene is bound to TDP-43 protein and allows it to stay in the nucleus.

Alexa Woo, PhD

However, when TDP-43 pathology is outside the nucleus, it decreases mitochondria function and synaptic integrity, connecting points between neurons. Researchers said synapse loss occurs in all neurodegenerative diseases.

This is an important step into the right direction, but researchers at USF Health agree that there is more work to be done.

“I think ultimately, if we can understand how the neurodegenerative disease leads to aberrations at the molecular level, then we can potentially target specific molecules that induce pathology in ALS or FTD,” Dr. Kang said.

Photos by V.  Hysenlika