Neurodegeneration research at the Waisman Center from gene to organelle to cell to brain

Neurodegenerative Disease Story Collage

By Charlene N. Rivera-Bonet, Waisman Science Writer

Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease, and retinitis pigmentosa all have different manifestations and affect different body functions, but they are all connected by one mechanism: neurodegeneration. They are characterized by the slow and progressive loss of neuronal cells in the brain or peripheral nervous system. Their main difference stems from which types of cells are particularly affected.

Researchers at the Waisman Center seek to unravel the specific mechanisms behind these and other neurodegenerative diseases with the goal of developing novel interventions.

Neurodegeneration and the secretory pathway

Luigi Puglielli, MD, PhD
Luigi Puglielli, MD, PhD

Many diseases across the lifespan are caused by an abnormal accumulation of protein aggregates in brain cells that become toxic, says Waisman Center investigator Luigi Puglielli, MD, PhD, professor in the Department of Medicine. For this reason, Puglielli’s lab focuses on the secretory pathway when studying neurodegeneration. The secretory pathway is the route through which cells secrete proteins into the extracellular environment, and it is essential for their normal function as an agent of quality control. A big player in the secretory pathway is the endoplasmic reticulum (ER), the first step of the pathway.

About 15 years ago, Puglielli shifted his attention to the ER and secretory pathway after stumbling upon its role in regulating protein homeostasis, or equilibrium, in the cell. “And we recognized at that point that the process that we had just uncovered was important, because of the possible implications,” Puglielli says. Nothing was known about this pathway, so they worked to identify the individual components of the machinery and generated mouse models of its dysfunction.

After proteins are created inside the cell, two things need to happen. One is making sure the products are made the right way. For those that are not, like misfolded proteins, the cell needs to be able to get rid of them. If this “disposing system” is dysfunctional, it can lead to toxic accumulation of the misfolded proteins. Successful acetylation, or addition of an acetyl group, to proteins in the ER is an essential step for successful engagement of the secretory pathway. On the other hand, failure of this process has been linked to different neurodevelopmental and neurodegenerative diseases, such as segmental progerias and Alzheimer’s disease.

Creating mouse models with a dysfunction of the secretory pathway led the Puglielli lab to outcomes they didn’t expect such as strange phenotypes and biochemical activities. To dissect those, they started looking into the genetics of their mouse models. “So, we went, in 15 years, from being a biochemical lab to today being a mouse phenotypic lab. In this business, you always have to reinvent yourself,” Puglielli says. This reinvention has allowed him to discover the mechanism that regulates protein homeostasis within the secretory pathway, which was completely unknown. His lab also discovered a new metabolic pathway that allows crosstalk between organelles within the cell.

These discoveries have led into projects that seek to dissect the mechanisms that link the ER dysfunction to neurodevelopmental and neurodegenerative diseases, identify the molecular mechanisms of cognitive loss during aging and Alzheimer’s disease, and find drugs that can prevent or cure the disorders associated with a dysfunctional ER machinery.

Gene regulatory networks and neurodegeneration

John Svaren, PhD
John Svaren, PhD

Neurodegeneration doesn’t only affect cells in the brain, but also nerves in the periphery. Charcot-Marie-Tooth (CMT) disease, is an inherited neuropathy that affects the nerves that supply information from the brain and spinal cord to feet, legs, hands, and arms. “One thing that is unique about these cells is that they’re actually the longest cells in the body. Motor nerves start in your spinal cord, and they end up in your big toe. So, depending on how tall you are, a neuron can be a meter long. And so that makes those axons very vulnerable,” says John Svaren, PhD, professor of comparative biosciences.

This loss of nerve function seen in CMT stems from issues with the myelin sheath, a fatty substance that wraps around nerve axons to allow faster, more efficient communication between nerve cells. Instead of having thick myelin, people with CMT have thin myelin, which causes nerve impulses to go slower, and also makes nerves vulnerable to axon degeneration. Svaren’s work focuses on the cells that create myelin, called Schwann cells, and the genetic and epigenetic processes that regulate their function.

“We’re very much interested in those [mechanisms of neurodegeneration] and whether those kinds of mechanisms can be targeted to treat a disease like CMT,” Svaren says.

A significant focus of Svaren’s research is trying to develop new biomarkers of CMT in order to enable clinical trials. Because CMT is a slowly progressing disease, it takes a long time to know if a treatment is working or not. The Svaren lab has developed a skin biopsy assay that can be used to measure disease progression early in clinical trials. “That’s been a major emphasis that we are proud of,” Svaren says.

His lab is also interested in understanding what happens after a nerve injury, outside of the context of disease. “Whenever there’s trauma to nerves such as a cut or crash, what happens is that the axons on the distal side of the cut typically degenerate, and there can be some regeneration of nerves from that site. But that regeneration of nerves is not really efficient,” Svaren says. Schwann cells play an important role in this process of regeneration upon injury, and are being studied to identify injury-regulated enhancers of Schwann cells that could be modified to aid the recovery process.

In the past, the belief was that axons just died upon injury. “But there are actually biochemical programs and steps that can be taken to intervene. So, there’s a lot of excitement,” Svaren says.

Using machine learning to understand neurodegeneration

Daifeng Wang, PhD
Daifeng Wang, PhD

Svaren also collaborates with Daifeng Wang, PhD, associate professor of biostatistics and medical informatics and computer sciences, using machine learning to identify genetic networks that regulate Schwann cells.

Machine learning is the use of mathematical or computational models to analyze large volumes of data, find patterns, and make predictions. Datasets that include genetic and epigenetic activities across different scales, like Svaren’s, often involve a high volume of information that is intricate and interconnected. Wang’s work focuses on developing new machine learning algorithms to identify unseen patterns in the data, and then use those patterns to predict things like disease phenotypes, diagnosis, and progression.

Once predictions are made using the models, scientists can go back and use the model to interpret the underlying cellular and molecular mechanisms in neurodegenerative diseases. This is called interpretability of machine learning.

Svaren and Wang are interested in identifying regulatory elements of myelin-producing cells that could be possible targets of therapeutic gene editing, and also to identify the genetic circuits required for healthy myelin formation.

Wang is also studying other neurodegenerative diseases such as Alzheimer’s disease, looking at gene expression, and how genes work together as a network within neuronal and non-neuronal cells to affect disease. “We can find those genes and gene networks so that we can use them to build models to predict Alzheimer’s disease or clinical phenotypes,” Wang says. For instance, he is one of the PIs leading computational analyses in NIA PsychAD project to analyze population-level single-cell sequencing data and decipher how cell-type level gene regulatory networks affect the interplay of neuropsychiatric symptoms and Alzheimer’s progression. In this project, his lab is also developing several novel deep learning approaches to identify personalized disease cells, genes and gene networks in human brains.

Stem cells and neurodegeneration of motor cells

Su-Chun Zhang, MD, PhD
Su-Chun Zhang, MD, PhD

Su-Chun Zhang, MD, PhD, professor of neuroscience and neurology, made a discovery that opened the door to a new way of studying neurodegenerative diseases of the motor system. In 2002, he got a call from a gentleman who had ALS and challenged him to work on developing motor neurons, the main cells affected in ALS, from stem cells. At the time, Zhang had pioneered the development of neurons from embryonic stem cells.  Taking him up on the request, his lab became the first in the world to develop motor neurons from stem cells and now uses them to study ALS.“I think the interaction with patients has very much been the main driver for my research working on ALS and other neurodegenerative diseases,” Zhang says.

Zhang’s lab uses stem cells in three main ways: understanding disease mechanisms, screening for drugs, and treatment development.

Using induced pluripotent stem cells (iPSC) derived from individuals with ALS or Parkinson’s and differentiating them into motor neurons or dopamine neurons, Zhang’s lab looks at pathologic processes that are taking place on these cells that may be reflective of disease pathology in humans.

In addition to understanding disease mechanisms, stem cells obtained from individuals with a disease are also used to determine the effectiveness of drugs on treating human cells with the disease. “Stem cells are quite important because we can actually look into human cells directly. Because in the past, we could only use animals. Now you can actually look at humans,” Zhang says.

Because neurodegeneration is characterized by a loss of specialized neurons – in Parkinson’s disease it is the loss of dopamine neurons in the brain – Zhang’s lab developed a technique to implant dopamine neurons into the brain region affected by neuronal loss as a disease treatment. The study, done in monkeys, showed that monkeys that had dopamine neurons derived from their own stem cells implanted into their brains showed long-lasting improvement in symptoms. This treatment is now awaiting approval from the Food and Drug Administration (FDA) to begin clinical trials in humans. This will take several years.

Retinal degeneration and stem cells

David Gamm, MD, PhD
David Gamm, MD, PhD

When David Gamm, MD, PhD, professor of ophthalmology and visual sciences and director of the McPherson Eye Research Institute first established his lab, the field of stem cells was starting to show tremendous promise. “But no one really knew where it could go or if it could be harnessed to make rare, complex human cells like those found in the retina,” Gamm says. He believed stem cell biology had promise for helping patients that he saw in his clinics with incurable cases of visual impairment caused by retinitis pigmentosa and other retinal degenerative diseases.

In 2009, Gamm was the first to develop 3-dimensional retinal structures from stem cells. The structures, later termed “retinal organoids”, could be separated from the rest of the cells simply by their appearance, making them practical to work with.

Similar to Zhang’s work, Gamm’s lab uses stem cell-derived retinal cells to investigate the cellular and molecular events that occur during the differentiation of early human retinal cells precursors, or progenitors. His lab then uses the photoreceptors and other retinal cells and tissues to study inherited retinal diseases and test treatment strategies to save or replace the retinal cells that degenerate in these diseases.

Recently, the Gamm lab published research showing that retinal cells grown from stem cells can reach out and connect with neighbors, results that bring them one step closer to trials in humans with degenerative eye disorders.

Biomarkers of neurodegeneration

Bradley Christian, PhD
Bradley Christian, PhD

A well-known hallmark of Alzheimer’s disease is the aggregation of two proteins in brain cells: amyloid and tau. Scientists have found that aggregation of the amyloid protein can precede the development of symptoms of dementia by 20 years.

Back in 2007, a new positron emission tomography (PET) imaging technique was developed that allowed for imaging of amyloid plaques in the human brain. Before this, the only way to measure its accumulation was post-mortem. Through the studies that this new technology catapulted, done at Waisman and the University of Pittsburgh, to an investigation co-led by Bradley Christian, PhD, professor of medical physics and psychiatry that found that people with Down syndrome started to show the presence of amyloid in the brain at a much younger age than individuals without Down syndrome.

The gene responsible for the production of amyloid is found in the 21st chromosome. An extra copy of this chromosome is characteristic of Down syndrome, making individuals with Down syndrome more susceptible to the disease in addition to showing symptoms at a younger age. Christian’s work focuses on developing new methods for PET and neuroimaging to study Alzheimer’s disease in individuals with Down syndrome, as well as other neurodegenerative and neuropsychiatric disorders.

Using PET imaging, Christian’s lab can investigate early changes in the brain of individuals with Down syndrome to better understand Alzheimer’s disease etiology and mechanism.

Sigan Hartley, PhD
Sigan Hartley, PhD

Christian and Sigan Hartley, PhD, professor and 100 Women Chair in Human Ecology, lead the Alzheimer Biomarkers Consortium-Down Syndrome (ABC-DS) study at the Waisman Center. The goal of this study is to follow a cohort of adults with Down syndrome over time to identify biomarkers that may signal the onset of Alzheimer’s disease with the hope of using the biomarkers to inform clinical trials and improve the quality of life in people with Down syndrome and the general population. Some of these biomarkers include PET scans, brain anatomy scans using magnetic resonance imaging, and biofluid samples.

Born from unexpected discoveries, patient requests, or decades of work, research on neurodegeneration at the Waisman Center moves the needle toward a better understanding of neurodegenerative disease that brings hope for better treatments and interventions in the future.


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