URSO Student Fellowship

The URSO Student Fellowship supports students conducting summer research projects focused on PSP, CBD, and related diseases. This program is supported by the Paul and Ruth Urso Memorial Research Fund. The goal of this fellowship program is to encourage students at all post-secondary levels to pursue research in this field in the hope of making PSP or CBD a long-term area of research interest. Projects may be in basic, translational, clinical or epidemiological aspects of PSP and CBD.

How to Apply

Undergraduate, graduate, and medical students are eligible – as well as medical residents and clinical fellows. PhD students and postdoctoral fellows are not eligible for this program. The research must be performed under the supervision of a faculty mentor with expertise in the field. The maximum award is $3,000. Funds may be budgeted to cover the applicant’s stipend and research related expenses. Grantees will present the results of their research at the Annual CurePSP Research Symposium in the fall (typically mid-November) following their summer project. CurePSP will provide awardees travel and lodging expenses for the Symposium.

The application form including further guidelines and instructions can be downloaded here.

Applications must be submitted by email to Dr. Alex Klein at klein@curepsp.org. The submission deadline is January 31 of each year.

2018 Awards

Mentor: Dr. John W. Steele; Humboldt State University, Arcata, CA

Kyle H. Anthoney

Advancements in the field of molecular genetics have allowed scientists to take a new approach at discovering a cure for “incurable” neurodegenerative diseases such as progressive supranuclear palsy (PSP). Attention has shifted from the direct assault on the toxic buildup of tau proteins in the brain that are known to cause progression of these diseases. Little is known about the pathology and incorporated regulatory system known as the autophagy pathway. Intervention and prevention strategies may be implemented by way of autophagy regarding the disruption of autophagy-essential genes and the production of disease-like phenotypes and accelerated cell death in human neurons. Exposure of the autophagy pathway and its responsibility in the management of toxic proteins will be exploited using state-of-the-art gene editing CRISPR technology to visualize toxic tau aggregates as well as quantify the turnover of total tau in neuronal cells. The goals of this project: 1) To determine the role of autophagy in the clearance and turnover of tau in neurons; and 2) To determine whether regulation of autophagy positively impacts turnover of misfolded tau proteins, will assess our central hypothesis. Stable and viable cells that have the potential of disease inheritance can be developed and scrutinized through neural progenitor differentiation using induced pluripotent stem cells from a fully sequenced and published genome. Until now, efforts have targeted end products whereas here, inhibition at the source will be investigated as a model of disease. The development of more specific, safe, and effective therapies for neurodegenerative patients will result in the further advancement of studying PSP with the potential to save millions from their impending malevolent diseases.

Mentor: Dr. Kenneth Kosik; University of California, Santa Barbara, Goleta, CA

Mukund Hari

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are two of the many debilitating neurodegenerative diseases that exist today lacking any significant treatments. Both diseases, along with Alzheimer’s disease, are classified as a tauopathies. In healthy nerve cells, the microtubule associated protein tau exists at normal levels. However, the misfolding and accumulation into intracellular aggregates called “neurofibrillary tangles” (NFTs) is a hallmark of tauopathies. 

The sheer multitude of failed clinical trials indicates that the complex biological understanding of tau pathways that cause the disease is lacking. Previous research has failed to conclude anything about the role of tau uptake into neurons and aggregation in neurotoxicity. It is still unknown whether these pathways can be targeted to mitigate symptoms and/or treat the disease.

Our research group and other studies have previously shown that tau aggregates, or “seeds,” added from outside the cell can be integrated into cells and induce misfolding of pre-existing tau from inside the cell. The endogenous tau plays a key role in neuron hyperexcitabilty. To understand how tau regulates neuronal physiology, we will utilize multi-electrode arrays (MEAs) to record electrophysiological deficits with models of tau aggregation. This model utilizes transgenic mice that has a mutant human form of tau associated with PSP. Using this model and cultures from wild type mice we will examine if pathogenic tau seeds can influence any phenotypes and ask fundamental questions about how tau can regulate neuronal activity at the population level.

Mentor: Dr. John W. Steele; Humboldt State University, Arcata, CA

Michael A. Martinez

Tauopathies are a class of diseases characterized by the dysfunction of tau proteins, encoded by the MAPT gene, in neurons and sometimes glial cells. There are six major isoforms of tau, which are often categorized based on the alternative splicing of exon 10 in the MAPT gene resulting in either 3R or 4R tau isoforms – based on either three or four microtubule-binding repeats. These isoforms are expressed equally in healthy brain tissue, but demonstrate an unbalanced ratio of 3R/4R tau in diseased brain tissue. This imbalance is commonly accompanied by the hyperphosphorylation of tau leading to the formation of
neurofibrillary tangles, which are a defining characteristic in primary and secondary tauopathies such as Progressive Superanuclear Palsy (PSP) and Alzheimer’s Disease (AD). Understanding the biological mechanism for exon 10 splicing will greatly aid our understanding of these tauopathies, which ultimately result in neurodegeneration and death. Recent breakthroughs in CRISPR-based gene editing have led to the utilization of Cas13 for the targeting of RNA instead of DNA. Additionally, engineering of this
protein in Dr. Feng Zhang’s lab has resulted in enzymatically dead Cas13 fused to a Green Fluorescent
Protein (GFP) that can bind to mRNA transcripts for visualization in living cells. This tool provides tauopathy researchers with the ability to measure 3R/4R tau concentrations in cell cultures and samples in a way that was previously unavailable. To understand how these tools may be utilized for tau research we will test the capability of enzymatically dead Cas13 (dLwaCas13) to measure MAPT transcripts in iPSC derived neurons. We will also use enzymatically active Cas13 (LwaCas13) to knockdown all 4R encoding transcripts in neurons to induce and model 3R/4R tau imbalance. Ultimately, our goal is to establish these tools as a reliable platform for studying the development and progression of tauopathies for the
development of therapeutic treatments. 

Mentor: Dr. John W. Steele; Humboldt State University, Arcata, CA

Haley M. Nisson

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) belong to a class of diseases known as tauopathies. Tauopathies are caused by the misfolding of a protein, tau, which is necessary for the healthy functioning of neurons in the human brain. These misfolded proteins bunch together, resulting in reduced neuronal functioning, and in the long term, death of neurons. 

An enzyme causally linked to the misfolding of tau proteins is glycogen synthase kinase-3 beta (GSK-3 beta). This enzyme is necessary for the healthy functioning of tau as it plays a vital role of adding phosphate groups to the tau protein, a process known as phosphorylation. However, abnormal GSK-3 beta activity is linked to excessive phosphorylation of tau, resulting in bunches of unfunctional tau, a known cause of tauopathies. Lithium has been shown to inhibit of GSK-3 beta activity, both directly and indirectly [6]. Inhibition of this enzyme has been shown to promote cellular degradation of proteins known to cause tauopathies, but it is yet to be proven whether inhibition of GSK-3 beta results specifically in degradation of misfolded tau.

My research goal is to test, using previously engineered tauopathy-mimicking cell lines, whether lithium successfully inhibits GSK-3 beta activity, and if this inhibition results in increased cellular degradation of misfolded tau.  

2017 Awards

Role of Oligodendroglial & Astrocytic Tau Pathology in a PSP Model

Grantee: Jacob B. Kantorowitz; University of Pittsburgh School of Medicine

Mentor: Dr. Edward Burton; University of Pittsburgh School of Medicine

Lay Abstract

One of the major mechanisms underlying PSP is thought to involve a protein called “tau”. Tau is normally present in nerve cells of the human brain, but in PSP it accumulates in large clumps called “neurofibrillary tangles”. This is thought to be one reason that nerve cells become sick in PSP.

In addition to nerve cells, the human brain contains supporting cells called “glia” that are essential to keep nerve cells healthy and functional. Surprisingly, tau protein also accumulates in glial cells in PSP. It is not known if this causes the glial cells to stop functioning properly – if so, this might be an important mechanism for nerve cells becoming sick in PSP, since nerve cells are dependent on glial cells to stay healthy.

To test this possibility we have constructed an animal model that will allow us to work out whether nerve cells become sick when glial cells accumulate tau protein. The zebrafish is a small freshwater tropical fish that is commonly used as a genetic model in the laboratory. Since zebrafish are also vertebrates, their brains share a surprising degree of similarity to our brains, at both structural and biochemical levels (although the zebrafish brain is much smaller and simpler than ours, making it a good experimental model).

We previously showed that human tau protein can be made to accumulate in the brain nerve cells of a genetically-modified zebrafish, where it causes cell death, a movement disorder and eye movement problems similar to PSP. In this study, we will ask how accumulation of human tau protein in the glial cells of genetically-modified zebrafish affects the health of nerve cells. Our study will show whether loss of supporting cell function caused by tau accumulation is important in PSP, and whether this could be targeted for new therapies.

Targeting Rho Kinases for PSP and CBD Therapeutics 

Grantee: Benjamin D. Boros; University of Alabama at Birmingham

Mentor: Dr. Jeremy Herskowitz; University of Alabama at Birmingham

Lay Abstract

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that involve movement and cognitive dysfunction but have no effective treatments. The progression of these diseases involves the accumulation and aggregation of the microtubule-associated protein tau in neurons and glia of the cortex and basal ganglia. In PSP and CBD, an over-abundance of certain tau isoforms is believed to contribute to disease by causing a cellular imbalance. This accumulation of tau is proposed to be toxic to neurons and detrimental to synaptic integrity. Therapeutic strategies that both reduce harmful tau and reverse synaptic weakening may effectively combat neurodegeneration in PSP and CBD.

Most synaptic connections occur on protrusions from dendrites called dendritic spines. Abnormalities in dendritic spine number, shape, or size have been reported in neurologic disorders, including autism spectrum disorder, Parkinson’s disease, and schizophrenia. In tauopathies such as PSP and CBD, evidence suggests that synaptic degeneration is a contributor of pathogenesis, and therefore dendritic spine numbers and morphology are likely detrimentally altered.

Identifying targets with clinically-available drugs that both reduce tau production and promote synaptic strengthening has been challenging. Our research group has recently identified that levels of a Rho-associated protein (ROCKs) are elevated in PSP and CBD brains. Drug inhibitors of ROCKs are well tolerated in humans and clinically-approved to treat stroke, hypertension, and spinal cord injury. Our group recently identified that treating cultured neurons with ROCK inhibitors both reduces tau production and increases the numbers of dendritic spines. We hypothesize that ROCK inhibitors can be repurposed to combat the over-production of harmful tau isoforms and to reverse tau-induced changes in synaptic structure or number. We believe that the results from this grant will motivate future studies investigating ROCK inhibitors as therapeutic means to tackle PSP and CBD.

Results

Please click here to read more about Ben’s results.

iCRISPRa into Neurons to Regulate Autophagic Clearance of Tau

Grantee: Benjamin M. Woodruff; Humboldt State University, Arcata, CA

Mentor: Dr. John W. Steele; Humboldt State University, Arcata, CA

Lay Abstract

Progressive supranuclear palsy (PSP) is one of at least 13 neurodegenerative diseases classified as tauopathies, which are named after the protein tau that forms insoluble deposits in brain tissue, currently affecting more than 5.5 million Americans. Tauopathy is also observed in patients who encounter frequent and/or severe brain trauma, such as professional athletes and members of the military.

As of today, there is potential for investigation into the cell’s methods of clearing these tau aggregates. However, little is known about how human neurons regulate clearance in response to abnormal buildup of tau protein, in part due to the difficulty recreating the complex nature of tauopathies in mouse brain or in common cell culture models. The proposed study utilizes the differentiating capabilities of induced pluripotent stem cells (iPSCs), made from a skin biopsy taken from a healthy adult. iPSCs are used to form all cell types susceptible to degeneration in the 13 tauopathies.

Our focus will be on neurons and glial cells, the cells showing the greatest degree of accumulation of tau in PSP. Our iPSC line originates from a single healthy adult, but has been further modified to mimic a disease-like state by duplication in the gene responsible for production of tau protein. This cellular model will be used in conjunction with a modern gene editing technique called inducible-CRISPR-activation (iCRISPRa). This technique will allow us to target and artificially activate genes in the autophagy pathway, which is crucial for the survival and recycling of cellular debris in neurons and glial cells, and investigate how autophagy is regulated in response to an abnormal accumulation of tau protein.

The results of this work will allow us to probe the autophagy pathway of diseased neurons and glia in a way not previously possible and will also contribute to deeper fundamental understanding of neurobiology.

Results

Please click here to read more about Ben’s results.