Post Doc Fellowship Awards

Collin J. Anderson, PhD
University of Utah, Salt Lake City, UT

Development and mechanistic study of deep brain stimulation of dentate nucleus for the treatment of degenerative ataxia.

Degenerative cerebellar ataxias (DCAs), characterized by incoordination of gait, tremor and motor symptoms, affect 1 in 5,000 people worldwide. Many different causes exist, but each combines the progressive death of Purkinje cells, a common neuron in the cerebellum of the brain. Despite the number of people affected by DCAs and decades of research, treatment options are limited. The loss of Purkinje cells is currently irreversible and leads to changes in the way brain cells communicate, so for any treatment to be successful, it will need to partially reverse these communication changes.

Our team believes deep brain stimulation could provide a new form of successful therapy. Using rats that have a loss or Purkinje cells and exhibit tremors and lack of gait coordination, we plan to surgically implant electrodes to repeatedly electrically stimulate targets within the brain and treat DCAs. Deep brain stimulation is frequently used to treat neurological conditions such as Parkinson's disease, essential tremor, and numerous other neurological conditions. The therapy affects the activity of different stimulation targets within the brain in a way that partially restores healthy communication between neurons. The target choice for stimulation in our study will be the dentate nucleus. It is the most important region in the cerebellum for controlling motor activity, and DCAs alter its signaling in a way that leads to motor symptoms. In conjunction with the implantation of stimulating electrodes, we will also implant recording electrodes in the rats to record from numerous neurons simultaneously. Through these recordings, we hope to determine precisely what elements of neuron signaling directly lead to motor coordination symptoms.

This project represents the opportunity to not only prove the concept of a major treatment opportunity for degenerative cerebellar ataxias, but also to greatly enrich our understanding of the neurological changes that directly lead to associated motor symptoms.

 

Laura C. Bott, PhD
Northwestern University, Evanston, IL

Transcellular regulation of the proteostasis network in Spinocerebellar ataxia type 3
 

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an inherited neurodegenerative disorder that is caused by a mutation in ataxin-3. At present, effective treatment is not available for this disease, and researchers do not yet know how neuron dysfunction occurs. Ataxin-3 is present in many tissues, including in cells that are not neurons, and has a role in controlling protein abundance, folding, and transport (called protein homeostasis, or proteostasis). Maintaining protein homeostasis in the body is essential because imbalances in any of these processes can pose a danger to cell function and the health of organisms. We are planning to study protein homeostasis in the tissues of worms that have been genetically engineered to have SCA3. Detailed knowledge of cell type-specific events and regulation across tissues will not only help to improve our understanding of the disease, but also may lead to new treatments for SCA3—and perhaps other neurodegenerative diseases as well.


Jonathan Chen, PhD
Scripps Florida, Jupiter, FL

Rapid structure-based lead optimization of a small molecule drug that target r(CAG)exp
 

RNA repeat expansions in spinocerebellar ataxia (SCA) cause degeneration of neurons, which leads to loss of control of body movements. My project will:

(1) Characterize the relationship between the chemical structure of a lead (leading) compound and its ability to target overexpression of “CAG” repeats, which are thought to cause several types of SCA (2) Optimize dimeric compounds for bioactivity, selectivity and potency.

Dimeric compounds have enhanced affinity for a target RNA over a monomeric compound because binding of one module to the RNA brings a second module within close proximity to the RNA. This increases the chance of the two modules simultaneously binding to the RNA over two separate monomeric compounds.

The compounds investigated in this work will reverse the overexpression of “CAG” repeats associated with these SCAs.

 
Ravi Chopra, PhD
University of Michigan, Ann Arbor, Michigan

Identifying Dendro-Protective Ion Channels in Cerebellar Ataxia
 

Purkinje neurons are important brain cells in the cerebellum, the part of the brain that controls balance and coordination. In cerebellar ataxia, Purkinje neurons often break down and eventually die. This process begins with shriveling of the neurons’ dendrites, one of the structures that all neurons use to communicate with each other. Research has shown that the shriveling of Purkinje neuron dendrites play a role in how ataxia symptoms develop. However, researchers do not yet know exactly how and why dendrite shriveling happens.

All neurons show electrical activity, which they need to communicate with each other. This electrical activity occurs through the action of a class of proteins called ion channels. In previous studies, my team and I have shown that major changes in Purkinje cell ion channels occur with spinocerebellar ataxia 1 and 2 (SCA 1 and SCA 2). In particular, we have found that the electrical activity in the dendrites of Purkinje neurons changes, and that change could be causing dendrite shriveling. In this new study, we hope to find out which ion channels affect dendrite shriveling. The ultimate goal is to discover news therapies that can halt changes in the ion channels with SCA1 and SCA2—thus reducing ataxia symptoms.

 
James Orengo, MD, PhD
Baylor College of Medicine, Houston, TX

Unraveling the mechanisms of motor neuron degeneration in Spinocerebellar Ataxia, type1
 

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive loss of coordination of movements and clumsiness. Individuals affected by this disease typically die between 30 and 70 years of age. Although the majority of scientists study loss of coordination in SCA1, individuals with SCA1 actually die from complications related to weak muscles—not the loss of coordination. In particular, the muscles no longer function well enough for the individuals to breathe properly.

My team and I have developed a mouse model for SCA1 that copies the major symptoms of human disease. Based on my clinical background as a neuromuscular disease expert, I made the exciting observation that these mice display signs of muscle weakness as well. In particular, I noted small and sick muscles, breathing abnormalities and muscle stiffness in adult mice. The goals of my project are to examine the molecular changes in these mice that lead to muscle weakness and early death, so that new treatments can be developed.

 

Stephanie Seminara, MD
Massachusetts General Hospital, Boston, MA

Ataxia with hypogonadotropic hypogonadism due to ubiquitin ligase dysregulation
 

Our research team is investigating a disorder called Gordon Holmes Syndrome. This syndrome adversely affects memory, movement and reproduction. Through our team’s research, we have identified a gene (RNF216), which, when severely mutated, appears to cause Gordon Holmes Syndrome. To further explore the biology of RNF 216, we are studying mice who lack this protein. Our team hopes to use this mouse model to understand how abnormalities in this gene affect neurologic and reproductive health. The long-term goal is to develop better therapies to treat this syndrome more effectively.