Faculty Spotlight: Matthew Scaglione, PhD

As a graduate student, Matthew Scaglione, PhD, became interested in how the body made and destroyed proteins–and how these processes could go wrong in neurodegenerative disease. Now, as an assistant professor at Duke, his research straddles the intersections between neurology, molecular genetics, and microbiology to better understand how we might be able to develop treatments for these conditions. For this week’s spotlight interview, we talk to Scaglione about about how a cellular slime mold may help us develop treatments for Huntington’s disease, how the COVID-19 epidemic has changed his work and home life, and brewing beer and raising a family and a group of pullets when he’s not at Duke.

What were your pre-COVID-19 responsibilities within Duke and the Neurology Department?
I am an Assistant Professor who runs a research laboratory that focuses on understanding the underlying causes of neurodegenerative diseases. The laboratory largely focuses on understanding how protein quality control pathways recognize and handle misfolded proteins that accumulate in these diseases. I have the pleasure of working with graduate students, senior scientists, and research technicians on a daily basis. I have a secondary appointment in Neurology and have really enjoyed all of the great journal clubs, data updates, and talks that occur in the department.

How has the COVID-19 epidemic changed that work? What does a typical workday look like for you nowadays?
The epidemic has definitely changed my work schedule. I am working with my students to write up a couple manuscripts and reviews, all being coordinated with Zoom meetings a few times a week. We still have our weekly update meetings, journal clubs, and lab meetings via Zoom as well. The biggest change has been that I get to also be a tutor for a 2nd and 5th grader. It makes getting work done more challenging but has been rewarding as well.

Your primary appointment is with the Department of Molecular Genetics and Microbiology. How do this discipline and neurology complement each other in your research?
Our lab investigates an amoeba that we and others have found to be resistant to certain types of protein aggregation. Having appointments in both Molecular Genetics and Microbiology (MGM) and Neurology is the perfect mix for our laboratory. Our lab uses genetic approaches in this microbe to learn about potential ways to combat neurodegenerative diseases, so interacting with other labs that are interested in molecular genetics, microbiology, and neurology is the ideal fit for my group!

How did you get interested in this field? What do you think is the most exciting development in the field of neurodegeneration in the past 10 years (or the most exciting development we’ll see in the next decade?

I became really interested in how proteins were made and destroyed as a graduate student. While I was finishing up graduate school, I started reading about how proteins form clumps in most neurodegenerative disease and how this protein clumping may be the underlying cause of these diseases. This coupled with the lack of effective therapeutics for neurodegenerative disease piqued my interest.

I think one of the biggest developments in the past ten years has been the development of RNAi and antisense technologies. These technologies allows for suppression of the expression of the toxic proteins that cause neurodegenerative diseases. This has great potential to treat a variety of neurodegenerative diseases and these therapies are already in clinical trials. I also think this potential therapeutic highlights the need for continued investment in basic science. The whole idea for these therapies comes from basic science research done in the worm.

What is the focus of your current research? How will the results of this research help us better understand or treat neurodegenerative diseases?
Our lab is really interested in the model organism Dictyostelium discoideum (dicty), more commonly known as a cellular slime mold or the social ameoba. This organism has been studied for over 70 years because it has the unusual ability to switch from being a single cellular organism to being multicellular. Our lab is interested in dicty because they naturally contain long stretches of the same amino acid. In some diseases like Huntington’s disease these long strings of the same amino acid trigger protein clumping and neurodegeneration. We have found that unlike other organisms dicty are resistant to this protein clumping phenomenon. Our hope is that we can fully understand all the ways that dicty resist protein clumping then transform our findings into novel therapeutics.

How has the COVID-19 epidemic affected your life outside of Duke? What’s one positive strategy or resource you’ve found that helps you cope?
The epidemic has definitely changed my work schedule. I am working with my students to write up a couple manuscripts and reviews, all being coordinated with Zoom meetings a few times a week. We still have our weekly update meetings, journal clubs, and lab meetings via Zoom as well. The biggest change has been that I also am a tutor for a 2nd and 5th grader. It makes getting work done more challenging but has been rewarding as well.

What other passions or hobbies do you have outside of work?
Outside of work I love spending time with my family, gardening, cooking, brewing beer, and raising chickens.

M Scaglione

Scaglione and family enjoy the fruits of their efforts after designing themed costumes.

Duke Neurology Research Round Up, April 2020

NIH nerveWhat do a genetic analysis of the intersecting pathways between Alzheimer’s disease and depression, a national prize-winning essay examining the ethics of unionization for physicians, and a systematic review of the literature surrounding a new potential form of therapy for stroke recovery have in common? They’re all subjects of peer-reviewed journal articles written or co-written by members of the Neurology Department published this March.

In our latest “Research Round Up” installment we review each of the 11 articles members of our Department contributed to and provide links to the original studies themselves.

Ethics

  • Unionization poses many ethical issues for physicians, with the most important being how to collectively bargain without putting their patients at risk. Resident Danielle Howard, MD, wrote an essay outlining these dilemmas, how they impact vulnerable populations such as residents, and ways that unionization can cause no harm, or even benefit, to patients. This essay was the grand prize winner in  the American Medical Association’s Art of Medicine contest. Read it in the AMA’s Journal of Ethics here.

Stroke

  • Senior author Wuwei “Wayne” Feng, MD, MS, Carmen Graffagnino, MD, Shreyansh Shah, MD, and colleagues conducted a systematic review of the literature surrounding S-Nitrosoglutathione (GSNO), a nitric oxide donor that may offer neuroprotective and neuro-recovery effects. Their analysis of 6 animal and 4 human studies found GSNO provided significant benefits in both preclinical and clinical studies, indicating that this molecule offers potential as a new form of therapy. Read the full article in Experimental Neurology here.
  • Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications but conflicting reports on outcome after stroke. Senior author Michael “Luke” James, MD, Shreyansh Shah, MD, and colleagues evaluated whether pre–intracerebralhemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome in a large, multi-ethnic case-control cohort. They found that pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcomes after ICH. Read the full article in Stroke.
  • Stroke published a letter to the editor by resident Martin Weiss, MD, Shreyansh Shah, MD, and Wuwei “Wayne” Feng, MD wrote a letter discussing a recent article about calculating the hematoma volume of spontaneous intracerebral hemorrhage. Read that article here.

Translational Brain Sciences

  • Patients who have late-onset Alzheimer’s disease (LOAD) are more likely to have depression, and depressed patients are also more likely to develop LOAD, suggesting either a shared cause or intersecting pathways between the conditions. Lead authors Michael Lutz, PhD, and Ornit Chiba-Falek, PhD, as well as Julio Barrera, and Daniel Sprague, examined the overlapping genetic signatures underpinning the common phenotypic manifestations and inter-relationship between these two conditions. Read what they found in Translational Psychiatry.
  • Senior author Alexandra Badea, PhD, Richard O’Brien, MD, PhD, and colleagues wrote an article in Frontiers in Physics that  provides guidelines for new protocols in mouse models of neurological conditions. Read their evaluations of diffusion imaging protocols with various spatial and angular resolutions here.
  • A team including Al La Spada, MD, PhD, analyzed the progression of a mouse model of Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease, from both physiological and histological perspectives. Their analysis uncovered new information about alteration in muscle function in the condition and suggested routes for new muscle-targeted therapies. Read their article in Disease Models and Mechanisms.
  • Audrey Dickey, PhD, contributed to a new Journal of Neuroscience article found that inhibition of the dynamin-related protein 1 (Drp1) is neuroprotective. The article also identified Bβ2, a neuron-specific Drp1 activator, which may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke. Read that article here.

Neurocritical Care

  • Elevated systolic blood pressure after successful revascularization via endovascular therapy is a known predictor of poor outcome. However, the optimal SBP goal following EVT is still unknown. Christa Swisher, MD, Shreynash Shah, MD, Ovais Inamullah, MD, and Shareena Rahman, MD, were part of an international multicenter study that compared functional and safety outcomes between different systolic blood pressure goals after EVT with successful revascularization. They found correlations for improved outcomes with lower blood pressure in three designated intervals. Read the full study in Annals of Neurology.

Neuromuscular Disease

  • Familial, but not sporadic, forms of amoytrophic lateral sclerosis are associated with a structural variant within the sequestosome 1 gene, according to a new case-control study in Neurology Genetics written by Rick Bedlack, MD, PhD, and colleagues. Read that article here.

Sleep Disorders

  • In the latest issue of Neuromuscular Disorders, senior author Andrew Spector, MD, and former sleep fellow Raj Bhui, MD, present a case in which a patient with late-onset Pompe disease was able to discontinue positive airway pressure therapy for his obstructive sleep apnea after treatment with enzyme replacement therapy for his Pompe disease. It is likely that an improvement in muscle tone from the enzyme replacement therapy was sufficient to eliminate his obstructive sleep apnea. Read that article here.

Neuro-Oncology

Student Spotlight: Alexa Putka

PutkaThis week’s “Spotlight” interview shines on Alexa Putka, an undergraduate researcher in the lab of Audrey Dickey, PhD. Putka talks to us about the passion, puzzle-solving, and collaboration that motivate her work to help better understand and reduce the effects of Huntington’s and other neurodegenerative diseases. She also talks about how her recent research fellowship from the Huntington’s Disease Society of America, and enjoying reading, axe-throwing, and time with family when she’s not at Duke.

 

What are your current responsibilities within the Dickey lab? What does a typical day for you look like?
My current responsibilities vary depending on what experiments we are conducting, which means that my “typical day” is also highly fluid. However, while I am actively working on an experiment, I am highly focused on generating quality data. For example, my recent experiments involve live-cell imaging in neurons using fluorescent calcium indicators to understand the role of mitochondria in buffering calcium to mediate excitotoxicity in Huntington’s Disease (HD).

This project involved extensive research into how to use such calcium indicators, which translated to trial and error on my part in determining how to use these proteins for my experiment. I find this search for the most effective method to study a particular intracellular process to be one of the most exciting parts of my day-to-day research, as I have the opportunity to delve into the literature, further understand the conceptual basis for my experiment, and then compare what other researchers have done to fill in the gaps for my methodology. After generating data, I am able to learn about how to analyze it, fitting these pieces into the larger picture of the intracellular signaling pathways affected by HD.

What do you enjoy the most about your time in the Dickey lab?
My favorite part of research with Dr. Dickey is the pursuit of a solution—I enjoy the search for the pieces of the puzzle that fit together to uncover connections in intracellular pathways, which provide ever-growing strategies to ameliorate the effects of neurodegenerative diseases. I also enjoy working with Dr. Dickey and our other lab members. I find that everyone brings a different perspective to each problem, and the constant collaboration and support provides additional motivation for our research.

What’s the hardest part of your research?
Setbacks are one of the hardest parts about research. Oftentimes, results of an experiment are not what I would expect, and it can be difficult to discern exactly what went wrong. However, when I look at the situation from a different perspective, I view these setbacks as a challenge, a way to test my skills of scientific inquiry, and an opportunity to learn something new. When this occurs, I work with Dr. Dickey and the rest of our lab to understand what happened, and this collaboration provides me with renewed hope that we can find a way around the problem and learn how to use the setback to our advantage. These problems usually help us better understand the protein we are studying, as factors we hadn’t previously considered become important for future experiments.

What plans do you have for what you’d like to do after graduation? If you could have any job in the world, what would it be?
Next fall, I plan to apply to Neurobiology PhD programs. I am very interested in continuing to pursue work with neurodegenerative diseases and intracellular signaling pathways that contribute to disease, but ultimately, I hope graduate school will broaden my understanding of other biomedical science fields and current research.

After graduate school, I’m not completely sure what I want to do, but I hope to pursue research in an academic setting because I have a passion for working with students to introduce them to topics that excite me, and I hope to foster my love for science in future students.

You recently received a fellowship from the Huntington’s Disease Society of America to study a research topic related to Huntington’s. What research question are you examining, and how will those results help us better understand or treat Huntington’s?
I am very grateful for the HDSA in supporting my research with Dr. Dickey. My work aims to explore the cellular mechanisms of excitotoxicity in HD. Excitotoxicity occurs when unrestrained glutamatergic signaling, increased intracellular calcium levels, and disrupted BDNF trafficking cause mitochondrial failure and cell death. Preliminary results from our lab indicate that a nuclear transcription factor called PPAR-delta (PPARd) can act as a neuro-therapeutic agent and protect cells against excitotoxicity.

Since excitotoxicity has multiple components, we sought to determine the precise mechanism of PPARd. While these experiments are ongoing, they implicate PPARd in functioning through the excitotoxicity pathway to ameliorate HD pathologies, which means that this pathway can serve as the target of therapeutic agents. The hope is that we can use this research to develop drugs to alleviate the symptoms of patients suffering from HD.

What passions or hobbies do you have outside of Duke?

While I am a very busy student outside of my time in the lab, I greatly enjoy reading nonfiction books, working with incoming Duke students through a program that welcomes them to campus in the summer, and spending time with my friends and family. As an eccentric side note, I also went axe-throwing recently (bars featuring axe throwing seem to be a new trend), which was extremely fun and surprisingly not too difficult. Maybe that will become my new hobby!

Putka Chicago

Putka enjoys a visit to Chicago (above), as well as amateur axe-throwing, below.

Putka ax

Do you have a (non-headshot) photo of yourself that you can share?

Duke Neurology Research Round Up, January 2020

NIH EEGMembers of the Duke Department of Neurology contributed to nine studies in peer-reviewed journals published in December 2019. In the fields of neurodegeneration and neuromuscular disease, our faculty found potential new avenues for therapies for spinocerebellar ataxia type 7 (SCA7) and myasthenia gravis. Other studies by our faculty and housestaff answered important questions about how reductions in blood pressure affect outcomes for thrombectomy, outcomes for deep brain stimulation for patients with Parkinson’s, and other areas. Read summaries about each of these articles, and find links to the original studies below.

Neurodegeneration and Neurotherapeutics

  • New research sheds light on the origins of SCA7 and demonstrates effective new therapeutic pathways for SCA7 and the more than 40 other types of spinocerebellar ataxia. The study, which appears in Neuron, implicates metabolic dysregulation leading to altered calcium homeostasis in neurons as the underlying cause of cerebellar ataxias. Read it here.
  • La Spada also contributed to a new statement from the American College of Medical Genetics and Genomics that examined whether there was sufficient evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients. Read that full statement in Genetics in Medicine.

Stroke

  • Christa Swisher, MD, Shareena Rahman, MD, and Ovais Inamullah, MD, were part of a multicenter retrospective study that examined the associations between reductions in systolic blood pressure and mechanical thrombectomy. The analysis of nearly 1,400 patients found that reductions in systolic blood pressure were inversely associated with poor outcomes but not safety outcomes. Read the full article in the Journal of Neurointerventional Surgery.

Neuroimmunology

  • Existing normative flow cytometry data have several limitations, such as small sample sizes, incompletely described study populations, variable methodology, and limited depth for defining lymphocyte subpopulations. Jeffrey Guptill, MD, MHS, was the senior author of a study that provides resources to better compare and extract data for subjects across gender, race, and age group. Read that study in PLoS One.

Neuromuscular Disease

  • Therapies that target Th17 cells could be a fruitful avenue for helping patients with myasthenia gravis, according to a new study by senior author Jeff Guptill, MD, MHS, Karissa Gable, MD, Vern Juel, MD, Janice Massey, MD, Shruti Raja, MD, Lisa Hobson-Webb, MD, and Melissa Russo. The team found that  the transcription factor RoRy, reduced the frequency of Th17 cells without affecting other T helper subsets. Read that article in Experimental Neurology.

General Neuroscience

  • Miguel Nicolelis, MD, PhD, was the senior author an analysis in Scientific Reports that examined the pitfalls and shortcomings of rotational dynamics, a proposed type of neuronal processing that exists in organisms from leeches to primates. Read that article here.

Movement Disorders

  • Sneha Mantri, MD, MS, contributed to a nationwide analysis of readmission and post-operative outcomes for Parkinson’s patients who have had deep brain stimulation surgery. Their analysis of more than 6,000 patients found favorable short-term hospitalization rates after DBS as well as persistent socioeconomic disparities in DBS. Read the full study in Parkinsonism and Related Disorders here.

Memory Disorders

  • Andy Liu, MD, was the first author of a JAMA Neurology study that answers important questions about the neuropsychiatric symptoms associated with tuberous sclerosis. Their case control study found that adults with tuberous sclerosis had similar cognitive and behavioral difficulties, as well as similar cerebrospinal fluid biomarkers, than patients with frontotemporal dementia. Read that study here. 

Sleep Disorders

  • Transvenous phrenic nerve stimulation (PNS) shows promise as a treatment for central sleep apnea, according to a study in the Journal of Clinical Sleep Medicine. Andrew Spector, MD, and colleagues examined nearly 200 patients who had received transvenous PNS, finding that it significantly improved CAS severity, sleep quality, ventricular function and quality of life, regardless of whether patients had heart failure. Read their full study here.

Profiles in Brain Sciences: Andrew West, PhD

Even as our understanding of how factors like genetics, metabolomics, and the environment contribute to Parkinson’s disease has rapidly advanced over the past 20 years, there are still no disease-modifying therapies for Parkinson’s or almost any other neurodegenerative disease. The Duke Center for Neurodegeneration and Neurotherapeutics’ Andrew West, PhD, is working to change that. For our first “Profiles in Brain Sciences” interview of 2020, West talks to us about his multidisciplinary in this area and why he’s hopeful that we’ll see treatments for at least some forms of the condition over the next few years. He also talks about how targeting different therapies toward specific populations with Parkinson’s is more likely to be effective than a unified “magic bullet” approach.

How are you and your lab working to better understand Parkinson’s disease? What projects in this area are you working on at the moment?
We work to translate discoveries made in human genetic studies into meaningful therapies that slow or halt the progression of Parkinson’s disease. We work with a combination of model systems and biospecimens from the clinic to help guide our understanding of how Parkinson’s disease changes over time, how it varies from person to person, and who might best benefit from precision therapeutic approaches. Our recent efforts focus on understanding and translating therapies directed towards the most common genetic causes of Parkinson’s disease, mutations in a gene called LRRK2 (we pronounce it LARK-two). We are developing model systems surrounding LRRK2 which has effects both in inflammation pathways and in neurons susceptible to disease, evaluating new therapies in these models that will go into clinical trial, and biomarkers to help guide clinical efforts.

How will this research lead to better treatments or quality of life for patients living with these conditions?
There is yet no known therapy that slows or halts the progression of Parkinson’s disease. Any advance towards our goal of disease modification will be groundbreaking for the millions affected by Parkinson’s disease and related disorders. In many ways, we think Parkinson’s disease is less complex than other neurological conditions, so we expect development of therapies to combat Parkinson’s disease may help serve as a template to pursue therapies for other complex diseases.

In addition to the Duke Center for Neurodegeneration and Neurotherapeutics, your work also spans the Departments of Neurobiology and Pharmacology & Cancer Biology. How do each of these fields inform and contribute to your work?
Engaging complex disease requires complex approaches, and a multi-disciplinary approach helps address bottlenecks and gaps that otherwise would slow down or inhibit progress. We keep a close watch on what is happening in cancer biology, both in understanding the complexities of heterogeneous disease in diverse clinical populations and the dangers of over-simplification of model systems in guiding experimental direction. One of the dramatic positive lessons we are trying to import in Parkinson’s disease is the successful utilization of biomarkers in patient stratifies in cancer that can be the difference between a failed or successful clinical trial. Likewise, we try to use the best pharmacological agents and approaches we can, with the expertise here in the Department helping us optimize experiments. The neurobiology happening here at Duke in Parkinson’s disease focuses on the neuronal systems affected and outcomes that provide insight into both health and disease.

What do you see as the biggest change in how we understand Parkinson’s and neurodegeneration since you earned your doctorate?
We understand Parkinson’s as a disorder that ultimately affects most of the brain, with a diversity of possible disease origins from the gut to the olfactory system. The genes linked to heritable aspects of late-onset (typical) Parkinson’s disease appear to be coalescing around dysfunction of the endolysosomal system which can be complicated to probe and understand in model systems and can change with age in different cell types. Certainly the evidence is now overwhelming that the ‘beating heart’ of Parkinson’s disease, for most patients, appears to revolve around changes of a protein called alpha-synuclein, with LRRK2 and other genes like GBAI modifying how alpha-synuclein interacts in disease. Our models have improved as well as general scientific rigor around testing hypotheses, so we think the conditions are right for the first wave of disease-modifying therapies to be found in the next few years.

What important or exciting change(s) in this field do you see coming over the next decade?
I think the next ten years will herald the arrival of therapies that are developed initially for genetically-defined segments of Parkinson’s disease that will spill over into typical late-onset Parkinson’s disease guided by precision biomarker approaches. It is clear, at least to me, there will be no one magic pill or bullet that will help everyone with disease. Treatments, effective initially in tightly defined disease populations, will need to be combined into temporally defined in disease with patients biochemically categorized to predict therapeutic benefit in diverse populations of disease. Complex diseases require complex therapies, and right now Parkinson’s disease is a blank slate. I believe this will change soon.

What passions or hobbies do you have outside of the Department?
Inspired by shows on HGTV, DIY channel and the like, I am known to gut kitchens, bathrooms, and other rooms down to their studs and build them back up again. I enjoy learning about the latest developments in plumbing, electrical, and other systems that I can work with. I am probably most relaxed browsing the aisles of big-box hardware stores on the weekend. Perhaps it is nice to see the immediate fruits of projects that are vastly less complex and time consuming than those we do in the lab! I am very fortunate to have a loving (and patient) family with two girls in elementary school and my wife who is involved with clinical genetics. Since moving to Duke, we have acquired a small herd of fainting goats that provide entertainment, and I have ambitions for sheep and chickens soon!

Andrew West

Above, Andrew and Kristen West enjoy the Grand Canyon, while below, Georgia West grabs her father’s glasses.

A West glasses grabbing

 

New study sheds light into origins of neurodegenerative disease

New research has shed light on the origins of spinocerebellar ataxia type 7 (SCA7) and demonstrates effective new therapeutic pathways for SCA7 and the more than 40 other types of spinocerebellar ataxia. The study, which appears online Monday on the website of the journal Neuron, implicates metabolic dysregulation leading to altered calcium homeostasis in neurons as the underlying cause of cerebellar ataxias.

“This study not only tells us about how SCA7 begins at a basic mechanistic level,but it also provides a variety of therapeutic opportunities to treat SCA7 and other ataxias,” said Al La Spada, MD, PhD, professor of Neurology, Neurobiology, and Cell Biology, at the Duke School of Medicine, and the study’s senior author.

SCA7 is an inherited neurodegenerative disorder that causes progressive problems with vision, movement, and balance. Individuals with SCA7 have CAG-polyglutamine repeat expansions in one of their genes; these expansions lead to progressive neuronal death in the cerebellum. SCA7 has no cure or disease-modifying therapies.

La Spada and colleagues performed transcriptome analysis on mice living with SCA7. These mice displayed down-regulation of genes that controlled calcium flux and abnormal calcium-dependent membrane excitability in neurons in their cerebellum.

La Spada’s team also linked dysfunction of the protein Sirtuin 1 (Sirt1) in the development of cerebellar ataxia. Sirt1 is a  “master regulator” protein associated both with improved neuronal health and with reduced overall neurodegenerative effects associated with aging. La Spada’s team observed reduced activity of Sirt1 in SCA7 mice; this reduced activity was associated with depletion of NAD+, a molecule important for metabolic functions and for catalyzing the activity of numerous enzymes, including Sirt1.

When the team crossed mouse models of SCA7 with Sirt1 transgenic mice, they found improvements in cerebellar degeneration, calcium flux defects, and membrane excitability. They also found that NAD+ repletion rescued SCA7 disease phenotypes in both mouse models and human stem cell-derived neurons from patients.

These findings elucidate Sirt1’s role in neuroprotection by promoting calcium regulation and describe changes in  NAD+ metabolism that reduce the activity of Sirt1 in neurodegenerative disease.

“Sirt1 has been known to be neuroprotective, but it’s a little unclear as to why,” said Colleen Stoyas, PhD, first author of the study, and a postdoctoral fellow at the Genomics Institute of the Novartis Research Foundation in San Diego. “Tying NAD+ metabolism and Sirt1 activity to a crucial neuronal functional  pathway offers a handful of ways to intervene that could be potentially useful and practical to patients.”

In addition to Stoyas and La Spada, other authors include Vikram Shakkottai, David Bushart, Pawel Switonski, Akshay Alaghatta, Chenchen Niu, Mandheer Wadhwa, Haoran Huang, Alex Savchenko, Karim Gariani, Fang Xie, Joseph Delaney, Terry Gaasterland, Johan Auwerx, Jacqueline Ward and Mi-bo Tang.

Young to discuss sorting out Alzheimer’s disease on January 13

The University of Washington’s Jessica Young, PhD, will deliver the first DCNN Seminar of 2020 on  Monday January 13, from 1-2 p.m. in room 103 of the Bryan Research Building. A lunch and preseminar reception will begin at 12:30 p.m.  Young will deliver the lecture “Sorting it out: Stem cell modeling to understand genetic risk and endocytic network dysfunction in Alzheimer’s disease.”

Finding hope in darkness: Duke neurologist develops and tests new therapy to help understand and prevent neurodegenerative diseases

Alexandra Angelova was 16 when she began experiencing blurry vision and occasional dizzy spells. Instead of going away, her symptoms gradually grew worse. Now nearly a decade later, with her vision at one percent of its original strength and with balance problems that prevent standing or walking unassisted, these symptoms inform every aspect of her daily life.

Angelova gets around the house and walks her dog, Sunny, using a rollator, or seated walker. She presses her back against the wall for balance when going up and down stairs. Every item in her house has a set location so she can find it with her limited vision.

“I cannot perform many basic things which are normal for a healthy person,” Angelova said. “I have to plan every movement and how to do it–how to hold a fork, how to take a shower, and so on.”

Angelova’s case is typical for people with spinocerebellar ataxia type 7, or SCA7, a chronic, inherited neurodegenerative disease. A child with a parent with SCA7 has a 50 percent chance of inheriting the condition. It is caused by a genetic mutation which causes the body to produce a malformed, toxic version of a normally healthy protein.

People with SCA7 develop normally as children when the body has the ability to filter out these malformed proteins. But sometime during adolescence or adulthood this protective effect disappears. Without it, the malformed proteins destroy cells in the retinas and the cerebellum, the brain’s balance center, taking sight and coordination with them.

Symptoms of SCA7 gradually worsen over time, and there is no cure. Angelova has had to make a series of lifestyle adjustments to compensate. Her eyesight recently deteriorated to the point where she can no longer read books, so she has switched to audiobooks. Adjusting the display of her smartphone to heighten contrast and magnify words and images has allowed Angelova to communicate with family and the outside world.

She works to be as independent as possible, doing her own laundry, cleaning, and shopping, and other tasks, but it’s difficult.

“I insist on doing these things, because it makes me independent and I face these challenges with pleasure,” Angelova says.

Read the full story on Magnify, an online magazine from the Duke University School of Medicine.

Parkinson’s Disease: The Stars in Our Brains

By Angela Spivey / Photos by Alex Boerner

astrocyteMore than 10 million people worldwide—about 1 percent of people over age 60—live with Parkinson’s disease. There are treatments that can help control symptoms, but there is no cure.

The hallmark of the disease is the death of certain brain cells—neurons that produce dopamine. Most Parkinson’s researchers have focused on studying these cells. But what if the disease starts elsewhere? What if it involves not only neurons but other cells that interact with neurons? In particular, what role is played by astrocytes, star-shaped cells that nurture and help form the connections, or synapses, between the neurons?

That’s the question a team of Duke researchers led by Cagla Eroglu, PhD, associate professor of cell biology and neurobiology, is exploring, thanks to a $1 million grant from the Chan Zuckerberg Initiative.

Sitting in her office, Eroglu picks up an orange plastic object that resembles a piece of coral, its tentacles branching this way and that. “This is a model of a mouse astrocyte,” she says. “It can interact with 100,000 synapses at the same time.” Astrocytes, she explains, infiltrate the brain, touching everything within their reach. They communicate with its synapses, regulating blood flow and metabolism.

(This article originally appeared in the Duke Medical Alumni News. Read it in that location here.)

Astrocytes —from the Greek “astron,” meaning “star”—have traditionally been thought of as support cells. But that thinking is changing. “Since astrocytes are in such close contact and continuously communicating with synapses, we are beginning to appreciate that they are also fundamentally involved in regulating brain function,” Eroglu says.

Albert La Spada

Collaborating with Albert La Spada, MD, PhD, (rhight) Eroglu found that a certain gene known to be important in Parkinson’s is more highly expressed in astrocytes than in neurons. And when the researchers mutated that gene in astrocytes, they saw some intriguing changes. This still-unpublished work laid the foundation for their proposal to the Chan Zuckerberg Initiative, which is bringing together experimental scientists from divergent fields to take a fresh look at the causes of neurodegenerative disorders.

“There are vanishingly few papers that have delved into how astrocytes are contributing to the Parkinson’s disease process,” says La Spada, professor of neurology and vice chair of research for the Department of Neurology. “This is an area that’s been under-studied, and I think that the results that we’re generating are suggesting that it deserves more attention.” In addition to his long experience studying neurodegenerative diseases, La Spada brings expertise in growing astrocytes from induced pluripotent stem cells (IPSCs). That process starts by growing skin cells from a skin biopsy from a Parkinson’s patient. “Then we use what’s called a reprogramming protocol to basically revert them to stem cells that are pluripotent. Once you create the IPSCs, you could use them to make any cell you want—a muscle cell or a cardiac cell or a neuron or an astrocyte,” La Spada says. “The beauty of this is, it comes from the patient who has the disease of interest.

”His lab’s expertise will only grow because of the Chan Zuckerberg Initiative, which has formed focus groups for grantees around various areas, such as stem cell modeling, CRISPR gene-editing technology, bioinformatic analysis of data sets, and more. “We’re meeting other researchers from around the world who are doing really unique things. It’s a chance for us all to compare notes, and I think this will accelerate all of our endeavors,” La Spada says.

Nicole Calakos

Rounding out the team is Nicole Calakos, MD, PhD, a scientist and clinician who treats patients with movement disorders, including Parkinson’s. Calakos says that when she first met Eroglu, she was intrigued by her idea that since astrocytes are involved in sculpting the language of neurons, perhaps they play a role in the events that can lead to disease.

“Everybody has been fixated like a magnet on the idea that the problem is the neuron that’s dying,” Calakos says. “Cagla said, ‘Hey, let’s think outside of the box of that dead cell. Let’s consider whether astrocytes are like the soil around a plant, providing the nutrition, and allowing it to form roots, and maybe that is what’s broken.’ Why aren’t we even thinking about this critical piece of the brain?”

Eroglu puts it this way: “Maybe the problem is loss of connections between neurons, even before they die.”

Calakos says that part of the reason she came to Duke was the close intermingling of physicians and bench scientists. “Because of how the community is at Duke, Cagla and I had been exchanging ideas and collaborating over the years,” she says. “The Chan Zuckerberg grant is an opportunity to get together as a formal team. I think it’s really forward-thinking of them to have teams of basic scientists and practicing physicians all talking to each other.”

The Chan Zuckerberg Initiative was launched in December 2015 by Mark Zuckerberg, founder and CEO of Facebook, and Priscilla Chan, a pediatrician and founder and CEO of The Primary School in East Palo Alto. In addition to her clinical insight, Calakos brings expertise in electrophysiology—real-time recording and observation of electrical signals coming from brain cells. “We can listen to the language of synapses,” she says. “They speak in electrical currents, which we can measure.” Eroglu believes that by learning all they can about how astrocytes support synaptic development and health in the normal brain, they may find ways to stop neurodegenerative diseases like Parkinson’s.

Cagla Eroglu

“We are seeing aging as a part of development,” Eroglu says. “If your house is built on a strong base, then it might last longer. Whereas, if you build it in another way, it may be there for a while, but gradually start to break down.

“This doesn’t mean that we are destined to have neurodegeneration and we can’t do anything. We may be more predisposed to get the disease, but we may not get it if we have done something else in our lives that helps strengthen our brain. I strongly believe that there will be ways to stop neurodegeneration. We will find a way to strengthen the brain connections. If we can figure out the weakest link, then we could concentrate on solving that.”

Duke Neurology Research Round Up, August 2019

What do new candidates for effective, non-addictive treatments for pain relief, a review of the past 20 years of how repetitive transcranial magnetic stimulation affects cognition, and an examination of how stroke-like conditions respond to treatments for stroke have in common? They’re all the subjects of research published by members of the Duke Department of Neurology in the past month. Read more about each of the 11 articles authored (or co-authored) by members of our faculty in August 2019, and find links to the original publications below.

Research Techniques

  • In the latest issue of the Journal of Visualized Experiments (JOVE), senior authors Constanza Cortes, PhD and Virginia Wertman demonstrate a new, low-cost alternative to digitized gait analysis programs for research projects examining movement abnormalities in mice. This method offers speed, simplicity and the potential for longitudinal analysis compared to other methods. Al La Spada, MD, PhD, and Anastasie Gromova contributed to the video and article, which appears here.

Memory Disorders

  • Obesity has been consistently associated with impairments in neurocognition and greater dementia risk, but the underlying reasons for these links are not fully understood.James Burke, MD, PhD, and Kathie Welsh-Bohmer, PhD, were part of a team that examined the metabolic mechanisms that may be responsible for these associations. Their Journal of Alzheimer’s Disease article found that higher leptin resistance play a role. Read that story here.
  • Assessing an individual’s willingness to undergo a potentially risky treatment is complex and difficult, especially for individuals dealing with cognitive impairment. Brenda Plassman, PhD, contributed to a study that examined willingness to accept risky treatments for both individuals with cognitive impairment who received amyloid PET scans as well as the willingness of their care partners. Read what they found in Alzheimer’s Disease & Associated Disorders.
  • A new meta-analysis by a team including Simon Davis, PhD, reviews the published literature surrounding how repetitive transcranial magnetic stimulation affects cognitive processing over the past 20 years. The Neuroscience Behavioral Reviews article examined more than 120 studies. Read their findings here.

Stroke

  • Prompt treatment with intravenous tPA offers enormous benefits for patients with acute ischemic stroke. However the need to treat patients quickly means there is also a risk of administrating tPA to patients presenting with noncerebrovascular conditions that closely resemble stroke. Ying Xian, MD, PhD, was the senior author of a study that analyzed national data from nearly 73,000 patients in nearly 500 hospitals to examine the safety of tPA in stroke-like conditions. Read what they found in Circulation: Cardiovascular Quality and Outcomes.
  • Xian also contributed to an American Heart Journal study that examined the associations between two types of preceding oral anticoagulant (warfarin or DOACs) and in-hospital mortality in patients admitted with gastrointestinal bleeding. Their analysis of nearly 6,000 patients found no significant differences in mortality between these two treatments. Read the full study here.
  • Michael “Luke” James, MD was part of a team that investigated the association of computed tomography–based markers of cerebral small vessel disease with functional outcome and recovery after intracerebral hemorrhage. Read their article in the latest issue of Stroke.

Neuro-Oncology

  • Chemotherapy-induced nausea and vomiting is a persistent, distressing side effect of treatment for many glioma patients. Annick Desjardins, MD, Katy Peters, MD, PhD, and Dina Randazzo, MD, contributed to a randomized open-label phase 2 trial of prepitant plus ondansetron compared to ondansetron alone to reduce these symptoms in a group of glioma patients. Read that article in Supportive Care in Cancer.

Headache and Pain

  • The DN-9 peptide has been identified as a promising candidate in the quest for anti-pain medications that engage the opioid system without producing opioid side effects. A team including Wolfgang Liedtke, MD, PhD, and Yong Chen, PhD, now reports that peripheral application of DN-9 provides potent pain relief with minimal side effects. Read that article in the British Journal of Pharmacology.

Biomedical Engineering

  • Cellular therapeutics offer great potential for treating medical conditions, but these therapeutics need a way to be effectively and safely delivered to the proper tissue compartment. Tatiana Segura, PhD, contributed to a new study that examines the use of microporous annealed particle scaffolds for this purpose. Read that study here.

Neurogenetics

  • An individual’s risk for developing schizophrenia is linked with lower cognitive abilities, at both the phenotypic and genetic level. Ornit Chiba-Falek, PhD, was part of an international team that  analyzed existing genome-wide association studies (GWAS) in cognitive ability, education, and schizophrenia to examine the possible biological mechanisms for these trends. Read their results in the American Journal of Human Genetics.