RNA Institute Researcher Receives Prestigious Early Career Award to Study Cellular Processes Underlying Class of Rare Diseases

RNA Institute Postdoctoral Fellow Hannah Shorrock. Image provided.

ALBANY, N.Y. (April 27, 2023) — Hannah Shorrock, a postdoctoral fellow at The RNA Institute at the University at Albany, recently received a “Pathway to Independence Award” to support her project entitled “Mechanistic Basis for Non-Canonical Translation in Neurological Disease.”

Shorrock is studying the cellular processes underlying the class of genetic neurodegenerative diseases that includes various spinocerebellar ataxias, Huntington's disease, ALS and myotonic dystrophy. These diseases share a type of mutation called “CAG repeat expansions,” wherein a portion of genetic code repeats many times, disrupting normal cell functions and causing wide ranging symptoms throughout the body.

The nearly $200,000, two-year grant was awarded by the National Institute of Neurological Disorders & Stroke, a branch of the National Institutes of Health.

Breaking Down Repeat Expansions

DNA provides the instructions to cells to produce the many different proteins that comprise the human body and it is made up of the nucleotide bases adenine, thymine, guanine and cytosine. These bases pair together in different sequences to code for different proteins. When a mutation disrupts the proper sequence for making a certain protein, things go wrong in the cell, which can lead to disease.

“CAG repeat expansions” are caused by multiple copies of the DNA nucleotide sequence cytosine (C) - adenine (A) - guanine (G). This type of mutation causes essential RNAs and proteins to be produced with extra sections of genetic code, which inhibit their normal functioning. These “toxic” expansion proteins and RNAs can disrupt multiple cellular processes and affect all systems of the body.

“CAG expansion diseases are a group of genetic disorders caused by DNA repeating many times in a particular gene,” Shorrock said. “In an individual without a CAG expansion disease, a particular gene might have 10 to 20 CAGs in a row, which would be considered normal. However, when the stretch of repeats grows to 40 or more in a particular gene, this process could cause a CAG expansion disease.”

CAG expansions are responsible for spinocerebellar ataxia types 1, 2, 3, 6, 7, 12 and 17, which are the diseases at the center of Shorrock’s project. These diseases all affect the cerebellum — the part of the brain that “fine tunes” voluntary physical movement to ensure accuracy — as well as other brain regions including the brainstem, the region that connects and communicates between the brain and spinal cord.

In spinocerebellar ataxias, because the “fine-tuning” function of the cerebellum is lost, patients experience a loss of balance and coordination which impairs leg and hand mobility. These diseases can also affect speech and sight.

Each gene associated with a CAG expansion disorder has a particular “pathogenic threshold” that can occur without causing disease.

“When the number of repeats exceeds the pathogenic threshold, CAG repeat diseases occur,” Shorrock said. “Which disease occurs depends on the gene that contains the CAG repeat expansion mutation. For example, expansions above the pathogenic threshold in the huntingtin gene will cause Huntington’s disease; expansions above the pathogenic threshold in the ataxin 1, 2 and 3 genes cause spinocerebellar ataxia types 1, 2 and 3, respectively. People living with these diseases can experience wide-ranging symptoms, depending on the genes affected.”

Lost in Translation

The mechanism that Shorrock is zeroing in on in this study is a function of how the DNA message is turned into proteins, a process called “translation.”

“Repeat expansion mutations disrupt normal cell functioning and can cause many things to go wrong in a cell that lead to disease symptoms,” Shorrock said. “One such disruption is a form of abnormal translation — the process by which cells make proteins.”

For a cell to make a protein, the DNA sequence for that protein is first made into RNA. This RNA can then be recognized by the cellular machinery that performs translation and is used as a blueprint for making the protein.

“Typically, when a cell produces proteins, its translation machinery recognizes a trio of nucleotide bases called a ‘start codon,’ which signals the translation machinery to start making a protein. Every three bases of RNA that the translation machinery ‘reads’ code for a single amino acid, which is added onto the growing chain of amino acids that will eventually form a protein. Because three bases code for one amino acid, it is important to know which set of three bases to read.”

In a CAG repeat expansion disease, the translation machinery sometimes starts translation without the needed “AUG” start codon. This means that the CAG RNA sequence is read in three different ways — “CAG”, “AGC”, “GCA” — resulting in the production of three distinct proteins. These proteins, which have different repetitive regions, are toxic and cause problems in the cell. “Therapies that reduce levels of these toxic proteins have been shown to improve disease symptoms in animal models of repeat expansion diseases,” Shorrock said.

CAG expansion diseases make up a large portion of diseases within the broader “microsatellite expansion diseases” category. Shorrock and her mentor, Andy Berglund, director of the RNA Institute, hope that progress in this area will shine light on new targets for therapeutic interventions to help people living with these devastating diseases.