A USF Health study applies a new mouse model of tauopathy, which may help identify therapeutic targets for Alzheimer’s and other neurodegenerative diseases

TAMPA, Fla (April 20, 2021) — Chaperone protein imbalance can play a significant role in initiating toxic accumulation of tau in the aging brain – an early step in the development of Alzheimer’s disease and related neurodegenerative disorders known as tauopathies, a new preclinical study by University of South Florida Health (USF Health) neuroscientists suggests.

Laura Blair, PhD, assistant professor of molecular medicine at the USF Health Byrd Alzheimer’s Center, was principal investigator for the NIH-funded study published in Acta Neuropathologica Communications | Photo by Allison Long, USF Health Communications

In humans, misfolding of the protein tau leads to its toxic accumulation inside brain cells, the formation of these tau aggregates into hallmark neurofibrillary tangles, neuron death, and eventually symptoms of cognitive decline such as memory loss and diminished thinking skills.

In this study the USF Health Morsani College of Medicine researchers used mice that were not genetically modified (wild-type mice) to examine the effects of Aha1 and FKBP52, two co-chaperone proteins of heat shock protein Hsp90, in the aging brain. They modeled molecular chaperone imbalance by overexpressing production of Aha1 and FKBP52 in these old, wide-type mice. The findings, highlighted below, were reported April 8 in Acta Neuropathologica Communications.

Hsp90 is a chaperone protein abundant in neurons and other cells in the brain. Normally, co-chaperone proteins assist chaperone proteins in monitoring and sustaining the balance (homeostasis) of proteins critical to cell health.

“The chaperone protein network is your cell’s natural defense to maintain homeostasis throughout life, and this study emphasizes the importance of protecting that balance in the aging brain,” said principal investigator Laura Blair, PhD, an assistant professor of molecular medicine at the USF Health Byrd Alzheimer’s Center, Morsani College of Medicine. “We’re excited about using this new model of tauopathy in finding ways to restore chaperone protein balance to delay or stop the progression of Alzheimer’s and other neurodegenerative diseases.”

Dr. Blair along with the research paper’s co-lead authors Marangelie Criado-Marrero, PhD (left), a postdoctoral fellow, and Niat Gebru (center), a doctoral student. | Photo by Allison Long

Among their many quality-control functions, chaperone protein networks ensure proteins are folded to conform to the proper 3D shapes, transported precisely where needed to do their jobs, and pushed toward degradation if they are abnormally modified or no longer useful. Heat shock proteins like Hsp90, triggered when a cell is under stress, play a particularly important “triage” role in correcting protein misfolding to prevent aggregation.

“But in the aging brain, the balance of the chaperone proteins shifts and creates a system not working as efficiently as it normally would. Large numbers of the chaperone molecules decrease in expression, and a smaller but significant number increase in their expression,” Dr. Blair said.

Increasing age is the greatest known risk factor for Alzheimer’s disease. So, the USF Health team investigated whether increased levels of FKBP52 and Aha1 alone could initiate pathological features mimicking human Alzheimer’s disease in aged wild-type mice – those with no genetic manipulations predisposing their brains to abnormally increase tau aggregation.

Tau pathology resembling that seen in Alzheimer’s disease brains. | Image courtesy of Laura Blair laboratory, USF Health

Key findings from their new mouse model of tauopathy include:

• High levels of FKBP52, and to a lesser extent elevated levels of Aha1, increased tau accumulation over time in the aged, wild-type mice.

• The tau accumulation promoted by overexpression of FKBP52, but not Aha1, correlated with increased neuroinflammation through exaggerated activation of neuronal support cells, namely microglia and astrocytes. This was complemented by loss of neurons and cognitive impairments.

Existing mouse models, including those that add or subtract genes, introduce tau mutations, and seed mice brains with human tau, help scientists learn more about the underlying causes of Alzheimer’s disease and other tauopathies. However, they tend to be limited in capturing the physiological aspects of neurodegeneration in the context of both normal and abnormal aging.

“We hope this (chaperone imbalance) model will help us better understand the dynamics of tau aggregation and neuroinflammation, including the timing and connections among pathological events, without directly regulating one pathway or the other,” Dr. Blair said.

Dr. Blair’s team has designed follow-up studies to help unravel if, and when, tau accumulation or neuroinflammation is more influential in causing brain cell toxicity during aging. That could help determine which chaperones — FKBP52, Aha1, or others — may be the best therapeutic target options for restoring protein balance, she said.

Dr. Blair’s laboratory studies how various chaperone proteins interact, for better or worse, with different forms of tau – ranging from soluble tau protein that can spread from one brain cell to another to the aggregated, misfolded neurofibrillary tangles inside brain cells.

Co-lead authors for the USF Health study were postdoctoral fellow Marangelie Criado-Marrero, PhD, and doctoral student Niat Gebru. The research was supported by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health.

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.

Preclinical study by a University of South Florida Health-University of Chicago research team offers new insights into how neuronal protein BIN1 may boost Alzheimer’s disease risk

TAMPA, Fla (March 11, 2020) — Bridging integrator 1, known as BIN1, is the second most common risk factor for late-onset Alzheimer’s disease, according to genome-wide studies of genetic variants. Yet, scientists know little about what this protein does in the brain.

Now a new preclinical study has discovered that a lack of BIN1 leads to a defect in the transmission of neurotransmitters that activate the brain cell communication allowing us to think, remember and behave. Led by Gopal Thinakaran, PhD, of the University of South Florida Health (USF Health) Morsani College of Medicine and colleagues at the University of Chicago, the study was published March 10 in Cell Reports.

USF Health’s Gopal Thinakaran, PhD, leads one of the few groups around the country studying BIN1 as a risk factor for late-onset Alzheimer’s disease. | Photo by Freddie Coleman

Approximately 40% of people with Alzheimer’s disease have one of three variations in the BIN1 gene – a glitch in a single DNA building block (nucleotide) that heightens their risk for the neurodegenerative disease, said the paper’s senior author Dr. Thinakaran, a professor of molecular medicine at the USF Health Byrd Alzheimer’s Center and associate dean for neuroscience research at the Morsani College of Medicine.

“Our findings that BIN1 localizes right at the point of presynaptic communication and may be precisely regulating neurotransmitter vesicle release brings us much closer to understanding how BIN1 could exert its function as a common risk factor for Alzheimer’s disease,” Dr. Thinakaran said. “We suspect it helps control how efficiently neurons communicate and may have a profound impact on memory consolidation – the process that transforms recent learned experiences into long-term memory.”

The research team created a mouse model in which the BIN1 gene was selectively inactivated, or knocked out, to characterize the protein’s normal function in the brain. In particular, they used advanced cell and molecular biology techniques to investigate the role of BIN1 in regulating synapses associated with learning and memory.

Peering into the brain, one synapse at a time: Electron micrograph shows selected region of a mouse brain hippocampus, the brain area responsible for learning and memory. A single synapse is marked with the yellow outline. | Image courtesy of Gopal Thinakaran, USF Health Morsani College of Medicine

To frame the study results, it helps to know that a healthy human brain contains tens of billions of brain cells (neurons) that process and transmit chemical messages (neurotransmitters) across a tiny gap between neurons called a synapse. In the Alzheimer’s disease brain, this synaptic communication is destroyed, progressively killing neurons and ultimately causing a steep decline in memory as well as other signs of dementia. Individuals most susceptible to developing full-blown Alzheimer’s in later life are those who lose the most synapses, Dr. Thinakaran said.

Among the Cell Reports study highlights:

• Loss of BIN1 expression in neurons leads to impaired spatial learning and memory. That is, the deficit alters how effectively information about surrounding environmental space is acquired, stored, organized and used. The BIN1 knockout mice had significantly more difficulty than controls in finding the hidden platform in a Morris water maze.
• Further analysis found that BIN1 is primarily located on neurons that send neurotransmitters across the synapse (presynaptic sites) rather than residing on those neurons that receive the neurotransmitter messages (postsynaptic sites). Synaptic transmission in the hippocampus, a brain region associated primarily with memory, showed deterioration in the release of neurotransmitters from vesicles. Vesicles are bubble-like carriers that transfer neurotransmitters from presynaptic to postsynaptic neurons.
• The BIN1 deficiency was associated with reduced density of synapses and a decrease in the number of synaptic clusters in the knockout mice compared to controls.
• 3-D electron microscopy reconstruction of the synapses showed a significant accumulation of docked and reserve pools of synaptic vesicles in the BIN1 knockout mice. That indicates slower (less successful) release of neurotransmitters from their vesicles, the researchers suggest.

Super-resolution imaging of BIN1 (green) combined with pre- and postsynaptic sites. White arrows at right indicate the overlap between BIN1 and synapsin, a protein involved in regulating neurotransmitter release at synapses. | Image courtesy of Gopal Thinakaran, USF Health Morsani College of Medicine, appeared first in Cell Reports (supplementary materials) doi.org/10.1016/j.celrep.2020.02.026

The study authors conclude that altogether their work highlights a non-redundant role for neuronal BIN1 in presynaptic regulation and “opens new paths for the future investigation of the precise role of BIN1 as a risk factor in Alzheimer’s disease pathophysiology.”

The research was supported by grants from the National Institutes of Health, the Cure Alzheimer’s Fund, and the Alzheimer’s Association, as well as fellowships from the BrightFocus Foundation and the Illinois Department of Public Health.

A new tumor immunology computational tool created by USF medical student Boris Chobrutskiy may help improve the predictability and precision of cancer immune therapies. He is first author of a study recently reported in Oncogene.

3D-rendered illustration of T-cells of the immune system attacking growing cancer cells

In the last decade, several immunotherapy drugs have been approved that rev up the patient’s own immune system to selectively combat cancer. These revolutionary anticancer treatments have shown remarkable potential to prolong the lives of those with malignant melanoma, advanced lung cancers and other types of cancers – but not all patients benefit equally. Their widespread use has been limited by unpredictable response rates and autoimmune side effects, including occasional life-threatening inflammatory damage.

Researchers at the USF Health Morsani College of Medicine’s Department of Molecular Medicine study the complex interplay between tumors and immune cells. They wanted to better understand apparently contradictory reports about the positive and negative effects of immune response in low-grade gliomas (LGG), brain tumors that grow slowly but are deadly.

So, they used the federal genomics database The Cancer Genome Atlas and a sophisticated computational method developed by third-year USF Health medical student Boris Chobrutskiy to determine the chemical match (complementarity) between a type of immune cell known as T lymphocytes (T-cells) and tumor-specific antigens. In particular, they delved into how well patient-specific T lymphocyte receptors matched abnormal proteins (antigens) of the patient’s LGG tumor cells. These tumor antigens flag the immune system to recognize and attack the tumor cells as “non-self” invaders so they do not grow uncontrollably.

Based on Chobrutskiy’s chemical complementarity scoring system, the researchers found that patient survival rates significantly increased when LGG-associated immune cell receptors (specifically the amino acid sequences of complementarity-determining region-3, or CDR3) were a good match with the cancer’s mutated protein, a tumor antigen known as the isocitrate dehydrogenase-1 (IDH1) mutant. Of 100 patient cases scoring high matches, 80% of the patients were living more than five years following diagnosis. Conversely, for 158 patient cases with poor or no discernable matches, only 30% survived beyond five years.

The USF Health study, with Chobrutskiy as lead author, was reported recently in the high-impact journal Oncogene. The paper’s senior author George Blanck, PhD, USF Health professor of molecular medicine, said Chobrutskiy’s latest publication is “a potential game changer” for developing next-generation tumor immunology tools. It is the medical student’s 16^th peer-reviewed article with faculty mentor Dr. Blanck and other co-authors in the molecular medicine group.

Third-year USF Health medical student Boris Chobrutskiy with research mentor George Blanck, PhD, a professor of molecular medicine

“Boris’s big accomplishment — both a thought success and a computer programming success — was figuring out how to track down matches between the mutant protein in the cancer and the receptor on the T-cells (lymphocytes). “It’s like finding two matching needles from two different haystacks,” Dr. Blanck said. “He was able to bring the chemistry of what’s happening in the body (with cancer-immune cell interactions) into the computer.”

Computational models like the one created by Chobrutskiy could improve the reliability of prognoses for LGG and other cancers — that is, the ability to predict whether existing checkpoint inhibitors or other cancer immune therapies will benefit a patient, Dr. Blanck said. “That could save a lot of patients from a potentially harsh reaction to an immunotherapy that does nothing for them.”

Clinicians already know that the absence of an IDH1 mutation represents a poor prognosis for LGG. However, the USF Health researchers suggest, a scoring system like Chobrutskiy’s, that can distinguish how effectively the immune receptors complement the IDH1 mutants, adds prognostic value and may help guide therapy for those patients who do carry the mutation.

Ultimately, advanced technologies characterizing cancer immunity could also be used to develop more precise therapies to kill targeted tumor cells while sparing healthy cells, preventing the extensive inflammation caused by an immune system in overdrive, Chobrutskiy said. “It’s an opportunity to personalize treatment for both a patient’s cancer with its unique mutations that drive tumor growth, and for the patient’s particular lymphocyte (T cell) repertoire.

Unlike other immune cells with largely genetically identical receptors, every mature lymphocyte has a unique receptor on its cell membrane. When an antigen invades the body, normally only those lymphocytes with receptors that best fit the contours of that particular antigen mount the immune response. This receptor diversity enables the lymphocyte to recognize and bind hopefully at least one antigen, whether the invading pathogen is a bacteria, virus, or cancer cell.

Chobrutskiy harnessed the power of Big Data and created an algorithm to track down  matches between the mutant protein in the cancer and the receptor on the immune cells. “It’s like finding two matching needles from two different haystacks,” Dr. Blanck says.

Since we have so many unique lymphoctyes and no two tumors are alike, “you really need a computer tool to sift through all the data and do the chemistry and math calculations to figure out the best matches,” said Chobrutskiy, who does computer programming as a hobby. “Finding the matches (between immune receptors and tumor mutants) in the laboratory would be way too expensive and time-consuming with such a large number of samples.”

The USF Health researchers will next test their hypothesis that patients with LGG who respond well to checkpoint inhibitor drugs will be those with highly specific binding interactions, or the “best fits,” between their immune cell receptors and tumor mutants.

“We know that their immune systems are already poised to go, whereas in the patient with no match, it doesn’t matter how well the T-cell works or how much you ‘uninhibit’ the T-cell,” Dr. Blanck said. “There’s nothing for the T-cell to do, because without a match even a boosted immune system cannot get rid of the cancer.”

The study was supported in part by USF Research Computing and MCOM Research, Innovation & Scholarly Endeavors fellowships.

-Photos by Freddie Coleman, 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

USF Health neuroscientist Chad Dickey, PhD — a leading NIH-funded researcher in the Morsani College of Medicine who developed an international reputation seeking answers to some of the most fundamental questions about neurodegenerative disorders, particularly Alzheimer’s disease – died Nov. 25, after a courageous battle with cancer.  He was 40.

“Many of us were truly privileged to work with Dr. Dickey, who was a brilliant neuroscientist bursting with creativity and a passion for discovery and scientific collaboration,” said Charles J. Lockwood, senior vice president for USF Health and dean of the Morsani College of Medicine. “He accomplished more in a decade than most investigators achieve in far longer tenure.

“We honor the outstanding scientific legacy Chad has left for us to build upon. He will be greatly missed, and his memory will live on in his many discoveries.”

Dr. Dickey was an associate professor of molecular medicine and psychiatry and a research scientist at James A. Haley Veterans’ Hospital.

While his impact on the field of neurosciences reached worldwide, his roots were planted firmly at the University of South Florida.  A Tampa native, he obtained both his bachelor’s degree in microbiology and PhD in pharmacology and neuroscience from USF. After completing a postdoctoral fellowship in neuroscience from the Mayo Clinic in Jacksonville, he returned to USF as a faculty member in 2006.

Dr. Dickey’s early work was as a member of a team that determined a vaccine may be a useful approach to treating Alzheimer’s disease.  He was the first to find that proteins involved in learning and memory were selectively impaired in mouse models of Alzheimer’s.

Much of his recent NIH-supported work focused on defects in the removal of damaged proteins by cells. Dr. Dickey’s promising studies of the key role “chaperone proteins” play in brain cell function were originally directed at Alzheimer’s disease, but subsequently expanded to other disorders ranging from glaucoma to depression to preterm birth. He wanted to find drugs to reverse defects leading to the buildup of harmful substances in the brain known as “tau tangles,” which are linked to the progression of Alzheimer’s disease — and he made considerable progress in that quest.

Dr. Dickey worked with Dave Morgan, PhD, for all but two of the last 17 years.

“He was a PhD student, research associate and research assistant professor in our laboratory. And for the last seven years he was a star faculty member in the Byrd Alzheimer’s Institute and Department of Molecular Medicine,” said Dr. Morgan, Distinguished USF Health Professor and CEO of the USF Health Byrd Alzheimer’s Institute.  “Thus, his loss is especially personal to me.”

Over his academic career, Dr. Dickey received 20 grants totaling more than $15 million from the NIH, Alzheimer’s Association and other organizations and published 65 scientific papers cited more than 4,000 times by other researchers.

“Equally important, Chad has trained an impressive group of PhD students and postdoctoral fellows, many of whom have gone on to successful biomedical research careers and will carry on his legacy,” said Robert Deschenes, PhD, professor and chair of the Department of Molecular Medicine.

Many colleagues and students have expressed an outpouring of sympathy and sadness upon learning of Dr. Dickey’s passing.

Edwin Weeber, PhD, a professor of molecular pharmacology and physiology and chief scientific officer at the Byrd Alzheimer’s Institute, admired his friend and colleague’s unflagging collaborative approach as a lead investigator.

“What I remember most about Chad was his constant smile, morning, noon and night. He was always in a pleasant mood, and his door was open to everyone,” Dr. Weeber said.  “Regardless of whether he was under the pressure of a grant deadline or preparing for a lecture, he always made time for you, even if it was just to chat.  Beyond his scientific acumen, he found a way to successfully balance the rigors of being a friend and colleague, a husband and father, and a scientist.”

Former doctoral student John O’Leary said Dr. Dickey helped him grow into a professional when he entered his lab at age 23 — supporting him through difficult times, and accepting his ultimate decision to leave academic science to become a jazz musician.

“He taught me how to work hard, and what it meant to have drive and passion. Once I was having a bad day and decided to escape the lab for a bit, and Chad found me eating a six pack of donuts in my black Yaris, in the parking lot of the Byrd at 11 am; I was so embarrassed. Although, he didn’t say anything, he didn’t have to. I knew his expectations for me were high,” O’Leary said.

“He pushed me to go beyond my comfort zone and continually challenged me in my learning as a scientist, a speaker, a thinker, a doer,” O’Leary said. “However, he was equally goofy as he was intense. One of my favorite memories is of him rapping Coolio’s “Gangsters Paradise” while doing bench work.”

Jose Abisambra, PhD, a former postdoctoral scholar in Dr. Dickey’s laboratory, now an assistant professor at the University of Kentucky Sanders-Brown Center on Aging, said that as a mentor Dr. Dickey led by example.

“During late nights, we would sometimes find him in his office writing a grant. Despite being so young, Dr. Dickey offered wise advice from overcoming challenges in the lab and in life; I learned how to successfully balance a family and an exceptional career,” Dr. Abisambra said.

“After completing my postdoctoral training in his lab, I founded my own research group, and our success is based on the tenants of impeccable work ethic, creativity, collaboration, and gratefulness, which I learned from him… He profoundly impacted my life as a scientist and as a person. I am certain that all of us who were fortunate to have trained with Chad will strive to carry out his legacy both in and out of the lab.”

Visitation will take place 10 a.m., Friday, Dec. 2, followed by a memorial service at 11 am, all at Idlewild Baptist Church in Lutz.  In lieu of flowers, donations can be made to the Dickey Education Fund to aid in the future education costs of Chad and his wife Adria’s two sons. For more information, please visit: https://www.youcaring.com/adrialukeandjakedickey-701981

For the obituary and guest book, click here.

Photos by Eric Younghans, USF Health Communications

The neglected parasitic infection that USF Health microbiologist Michael White, PhD, has spent the last 20 years studying causes few, if any, symptoms in healthy people.  But the disease caused by the malaria-related parasite T. gondii, known as toxoplasmosis, can cause life-threatening illness  in people with weakened immune systems, such as those with HIV/AIDS, the elderly and babies born to women infected during pregnancy.

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“Toxoplasma can be a dangerous infection that’s easy to overlook, because it’s not filling our emergency rooms,” said Dr. White a professor of molecular medicine and global health and one of the world’s leading experts on the malaria-related parasite. “But it’s a potential time bomb.”

Michael White, PhD, is one of the world’s leading experts on the malaria-related parasites T. gondii.

 Listen to Dr. White talk about how the process of science is like a puzzle.

People can acquire toxoplasmosis several ways — usually by direct exposure to the feces of cats or by eating undercooked meat of an infected animal, or drinking water contaminated with the organism.  Up to 15 percent of the world’s population is estimated to be infected with T. gondii, and in some parts of the world where sanitation is poor and eating raw or undercooked meat is customary, nearly all people carry the parasite, Dr. White said. In Brazil, particularly virulent strains of the parasite cause a high-incidence of vision-threatening eye disease.

Because the organism is common, relatively easy to disseminate and not easily killed with standard disinfection measures, the National Institutes of Health cites the toxoplasma parasite as a potential threat to national security and public health.

Dr. White is deputy director of the Florida Center of Excellence in Drug Discovery and Innovation at USF.  His research team combines genetic, biochemical and cell biology approaches to understand how the parasite replicates, establishes chronic infection and interacts with host cells. Their goal is to find new ways to combat the pervasive parasite, which has both rapidly dividing acute stage destructive to healthy tissue and a chronic stage where egg-like cysts remain invisible to the immune system, basically hiding out in brain or muscle tissues to avoid attack.

No drugs or vaccines currently exist to treat or prevent the chronic, or dormant, stage of the disease.

Dr. White with his research team at the USF-based Florida Center of Excellence in Drug Discovery and Innovation. From left: Jeanine Yacoub, graduate student in the Department of Chemistry; Dong-Pyo Hong, PhD, assistant professor; Elena Suvorova, PhD; assistant professor; Carmelo Alvarez, MS, research technician; and Anatoli Naumov, PhD, assistant professor.

“A major clinical challenge with toxoplasmosis is that the T. gondii cysts can quietly slip into into your brain or muscle cells, where they can settle without growing” until weakened immunity reactivates the disease, Dr. White said.  “The drugs used to treat toxoplasma infections only attack growth, so they do not cure the lifelong infection. They help reduce the danger of acute infection for AIDS patients or others with compromised immune systems.”

In the past several years Dr. White’s laboratory, working with partners at the University of Georgia, made several intriguing discoveries about the growth and development of the malaria-related parasite. Their work with T. gondii may also lead to new therapies to combat drug-resistant strains of malaria, a mosquito-borne tropical disease threatening to resurge as a public health crisis in certain parts of the world.

To understand the Toxoplasma research, it helps to know that ages ago the ancestors of malaria parasites genetically merged with an ancestor of plants, and the primitive plant donated proteins known as AP2 factors to the future malaria family. Also, unlike plant and animal species – where chromosomes get one shot at replication or else the cell dies or turns into cancer – these malaria-related parasites manage to multiply exponentially while avoiding cell death.

Dr. White, with colleague Dr. Elena Suvorova, conducts NIH-funded research investigating molecular mechanisms underlying the growth and development of T. gondii with the aim of eradicating the pervasive malaria-related parasite.

 Dr. White comments on the role of failure in science.

In a 2013 study appearing in the Proceedings of the National Academy of Sciences, Dr. White’s team demonstrated that AP2 factors are instrumental in flipping a developmental “switch” that transitions T. gondii from its acute to dormant stage.  The USF study showed that, like the AP2 factors that help a plant survive in stressful environments including poor water or soil conditions, the AP2 factors of T gondii help regulate when the time is right to grow or when to form tissue cysts that may lie dormant in people for many years before the host immune system detects their presence.

Dr. White and colleagues were also the first to uncover part of the mysterious process by which T. gondii spreads at explosive and potentially deadly rates inside humans and other animals. In a study published this spring in the high-impact journal PLOS Biology, the researchers discovered how these ancient parasites pull off replicating their chromosomes hundreds or even thousands of times before spinning off into daughter cells with perfect similitude.

The explanation: Toxoplasma parasites have a modified “control room,” called the centrosome, which imposes order on the replication chaos, Dr. White said. “Unlike the comparatively simple centrosome present in human cells, the parasite ‘control room’ has two distinct operating machines: one machine controls chromosome copying, while the other machine regulates when to form daughter cell bodies. Working together, but with independent responsibilities, parasite centrosome machines can dictate the scale and timing of pathogen replication.”

Exposure by cleaning the litter box of an infected cat is one way in which the Toxoplasma parasite can be transmitted to humans. The tiny organism is transmitted to cats by rodents, and the parasite thrives in the cat’s gut, producing countless egg-like cells that are passed along in the feces.

Dr. White’s team found that the operation of the centrosome requires kinases, the same enzymes most effectively attacked by certain cancer drugs.  So far, they’ve identified within both centrosome machines six kinases that could be potential drug targets.

This new knowledge and the groundbreaking understanding of the centrosome’s function suggests that the system’s highly-efficient cell proliferation can be disrupted to kill the malaria-related parasites.

“These stealthy parasites evolved a more complex mechanism to control cell division, because they wanted to avoid the immune system — but they created a vulnerability in doing that,” Dr. White said.  “They are like Humpty Dumpty. When we hit one of the kinases, the parasite breaks apart and can’t be put back together… And if we can develop drugs to inhibit two or more of these critical kinases, then we could potentially overcome the problem of drug-resistant strains.”

The researchers have already begun screening small molecules to identify the best potential inhibitors of the centrosome kinases they’ve identified.

Dr. White in the High Throughput Screening Core at CDDI, where USF researchers screen small molecules to help identify the best inhibitors of the T. gondii centrosome kinases (potential drug targets) they’ve identified.

Dr. White’s laboratory has also discovered proteins that control expression of the chronic, or dormant, phase of toxoplasmosis. In animal model experiments, the researchers were able to alter parasite genes active in the acute phase of the disease to eliminate the “silent” stage of the disease, perhaps by “teaching” the immune system to combat the dormant stage, Dr. White said.

The work may lead to a vaccination to prevent the chronic stage of the disease in animals, which is one of the sources of infection for humans, he added.  “If we could eradicate the toxoplasma from poultry, pigs and other livestock, we could help break the cycle of transmission from the food supply (to humans).”

Dr. White joined USF in 2009 from Montana State University where he was a professor of veterinary molecular biology. He received his PhD in microbiology from Oregon University in 1983, and completed a postdoctoral research fellowship at the University of Washington focusing on how to attack the growth of cancer cells. In the early 1990s, under the mentorship of electron microscopist C.A. Speer at Montana State, his research emphasis shifted to eukaryotic pathogens, parasites that can lead to a variety of diseases in humans, animals and plants.

Since 1996, he has investigated molecular mechanisms underlying the growth and development of T gondii with the aim of eradicating the malaria-related parasite using a two-pronged approach: reducing its proliferative capacity and breaking the cycle of transmission between animal and human. Across his career, Dr. White’s research has been continuously funded by grants from the U.S. Department of Agriculture and, since 1988, by grants from the National Institutes of Health. He is the principal investigator for two active NIH R01 grants totaling more than $4.8 million, with a third $2.6-million grant pending.

Image of Toxoplasma gondii parasites dividing provided by Ke Hu and John Murray (DOI: 10.1371/journal.ppat.0020020.g001). Dr. White and colleagues were the first to uncover part of the mysterious process by which T. gondii spreads at explosive and potentially deadly rates inside humans and other animals.

Dr. White chairs the NIH Pathogenic Eukaryotes Study Section and is a member of the Genome Consortium for Toxoplasma gondii. He serves as an ad-hoc reviewer for several journals, including PLoS Pathogens, Molecular Microbiology, and Eukaryotic Cell.

His laboratory, based in the USF Research Park, collaborates with USF medicinal chemist Jim Leahy, PhD, and he supports postdoctoral fellows at the University of Georgia and Indiana University School of Medicine.

Something you might not know about Dr. White:  As a teen growing up in Albuquerque, New Mexico, he raised Blue Dutch rabbits.  He also collected rattlesnakes, tarantulas and blue racers from the mesa bordering his home. “It was the only field biology I ever did,” he said.

Photos by Eric Younghans, USF Health Communications & Marketing

Yu Chen, PhD, an associate professor in the Morsani College of Medicine’s Department of Molecular Medicine, was among five USF faculty members who recently received the university’s Excellence in Innovation Awards for their exceptional research and innovation.

Each winner received a $2,000 award and plaque presented at the annual luncheon of the USF Chapter of the National Academy of Inventors on Aug. 31.

Yu Chen, PhD

The award recognizes Dr. Chen for his patented technology of novel beta-lactamase inhibitors licensed by Gordian Biotechnologies to tackle the growing problem of antibiotic resistance, for the development of collaborations with Achaogen Inc., and for his publications last year in the Journal of Medicinal Chemistry and Future Medicinal Chemistry.

Dr. Chen’s structure-based drug design approach has led to the development of novel small molecule inhibitors against multiple proteins involved in antibiotic resistance, metastatic cancer and Alzheimer’s disease. Using an interdisciplinary approach, he combines both computational and experimental techniques to investigate the function and inhibition of enzymes related to bacterial cell wall synthesis, the biological process targeted by antibiotics such as penicillin.

Dr. Chen has extensive experience in biochemistry, X-ray crystallography and molecular docking. He has characterized the catalytic mechanisms of three enzymes and determined about 40 crystal structures including protein complexes with DNA or small molecules.

The crystal of a protein used to help design better beta-lactamase inhibitors.

Science is full of precision and vigilance. But sometimes, there are subtleties that present themselves that get ignored, pushed aside for the drive to stay on task or to stick with the parameters of a hypothesis.

Michele Parry, a student in the Masters of Molecular Medicine Pre-Professional Program at the USF Health Morsani College of Medicine, was working for the former when she experienced the latter. It was an “ah ha!” moment that ended up being a key finding for why certain genes of cancer cells mutate, while others don’t.

Michele Parry.

Parry volunteered in the lab of George Blanck, PhD, professor of molecular medicine, who was studying how the size of a gene’s protein coding region affects it’s the likelihood of becoming mutated. While combing over screen after screen of data – spreadsheets, graphs, and countless lists – she spotted a trend: larger genes are more frequently mutated than smaller ones, and in particular genes encoding cytoskeletal proteins.

“She spotted something that I didn’t and, thanks to that, we were able to run with it,” said Dr. Blanck, whose work looks into the nuances of genes and who pushes to fill the pipeline with talented biomedical sciences students.

The gene mutation work warranted publication, for which Parry was first author. It’s unusual for master’s students to be first author of published research, but Parry’s story is a good example of the experiences students in the USF master’s program can have, Dr. Blanck said.

“This is what master’s students in our program can do,” Dr. Blanck said.  “The role of the student in research is becoming more apparent. Nurturing that experience for a student researcher is directly connected to our mission of teaching.”

Titled “Big genes are big mutagen targets: A connection to cancerous, spherical cells?” in the September 2014 edition of Cancer Letters – the publication resulted in funding for new research looking into how the shape of cancer cells (round versus flat) affects drug resistance.

Dr. Blanck and Wade Sexton, MD, associate professor in the USF Department of Oncologic Sciences and a bladder cancer specialist at Moffitt Cancer Center, were awarded the Anna Valentine Award by Moffitt Cancer Center for new work titled “Cytoskeletal protein related coding region mutations in bladder cancer.”

“Cancers cell have unique characteristics and their shape may affect whether or not they are resistant to drugs,” said Parry.

Parry has a bachelor’s degree in biology and wants to be a physician. Specifically, she wants to be an oncologist. She’s driven to understand the difficult science and realizes she’s lucky to pick it up so fast.

“I’m happy that I’m educated and can understand a lot of this,” she said. “And tutoring the master’s students really helps me cement the molecular biology concepts. We’ll see if I feel the same way as a medical student.”

Parry applied to medical school once and was told to strengthen her resume to increase her likelihood of acceptance.

So, strengthen it she did. Since first applying to medical school in 2012, she has graduated with her master’s degree earning a 4.0 GPA, she now works in Dr. Blanck’s lab and has been published as first author, she is an adjunct professor at St. Petersburg College, and she is the graduate teaching assistant for the master’s program.

“This was supposed to be my year off,” she joked. “But I needed to do all of this to strengthen my candidacy and to prove I could excel at the graduate level.”

Was that “ah ha!” moment proof of her abilities? Parry describes it more as a chance to contribute to promising cancer research.

“It makes me feel valuable,” she said, “and gives me a sense of gratitude.”

Photos by Eric Younghans, USF Health Office of Communications

Watch City of Tampa TV show on Genomics at USF Health 

Genomics, the study of genes and their function, is a burgeoning field that is changing the face of medicine and other health professions as it gives practitioners, and even patients, unprecedented detail about diseases, conditions and even levels of health risk.

Beginning fall semester, USF Health will offer its first course in human genomics designed specifically for health professionals without advanced research training, including those in medicine, nursing, public health, pharmacy and physical therapy.

Human Genomics in Medicine and Public Health (PHC 6943/GMS 7930) will introduce genomics and modern genetic technologies to master’s-level and senior undergraduate health students with limited training in molecular biology and biochemistry.  The course, taught by genomics experts from the colleges of Medicine and Public Health, will integrate these rapidly developing technologies into the real-world practice of personal health decisions and public health initiatives encompassing population health.

The curriculum will cover information needed to meet nursing as well as public health competencies in genomics.

Michael White, PhD, professor of global health and technical director of the new course, says the human genome is an instruction manual for building and maintaining a human being.

Michael White, PhD

“Only very recently has medicine had the tools to translate the DNA language of the complete instruction manual. The manual for each of us has unique pages that together make up our individual book of life.  Today, understanding each book of life is within our grasp, and this has profound implications for our health,” said Dr. White, a practitioner of genomics and bioinformatics in research.

“It will fall to health professionals at all levels to help us navigate this new world of genomics and teach us to confidently read and understand our own book of life.”

Dr. White designed the curriculum with course clinical director Judith Ranells, MD, chief of the Division of Genetics and Metabolism in the USF Health Morsani College of Medicine and a practitioner of clinical genetics.

Judith Ranells, MD

“In this course we will train front-line health professionals how the new DNA decoding tools work and how genome-based knowledge will impact the future of individual health decisions, including the diagnosis, treatment and prevention of disease,” Dr. Ranells said. “We will also consider strategies for preventing the potential misuse of genomic information and ensuring patient confidentiality.”

Registration in currently open for Human Genomics in Medicine and Public Health, which will be held 5 to 7:45 p.m. on Wednesdays at the Interdisciplinary Research Building in the USF Research Park.  For more information, please contact either of the course directors: Dr. White at mwhite3@health.usf.edu or Dr. Ranells at juranell@health.usf.edu